The following season, Van Persie signed a three-and-a-half-year professional contract with Feyenoord, and scored five goals in a 6–1 KNVB Cup thrashing of AGOVV Apeldoorn on 6 February 2003. However, clashes with his manager Bert van Marwijk saw Van Persie demoted to the reserve squad. During a match featuring the Feyenoord and Ajax reserves, he was one of several Feyenoord players assaulted by hooligans who had invaded the pitch. Van Persie’s rift with Van Marwijk continued when he was sent home on the eve of the 2002 UEFA Super Cup final against Real Madrid after the coach was displeased with Van Persie’s body language after being asked to warm up for a Champions League qualifier. Van Persie finished his tumultuous first full season with the first team having scored eight goals in a total of 28 appearances, in addition to finishing runner-up in the KNVB Cup.

On 17 May 2004, Van Persie signed a four-year deal with Arsenal for £2.75 million, just over half of Feyenoord’s original asking price of £5 million. Arsenal manager Arsène Wenger, who planned to convert Van Persie from a left winger to a centre forward as he had successfully done with star player Thierry Henry, said of his new acquisition, “He can play on the left side of midfield, as a creative player behind the main strikers or as a target man.” Arsenal had further padded their stable of strikers in January by signing Spanish forward José Antonio Reyes, leaving the two to battle for playing time. Van Persie made his debut and won a trophy in the process, as he came on as a substitute in the 3–1 FA Community Shield victory over Manchester United on 8 August 2004. Van Persie spent most of his time on the bench during earlier parts of the 2004–05 season, and marked his first competitive start on 27 October by scoring Arsenal’s opening goal in a 2–1 League Cup win over Manchester City.

Van Persie was a U-21 international and took part in the 2004 and 2006 European Championship qualifying. Van Persie was used in a wider role as a left wing due to the preference of the experienced Klaas-Jan Huntelaar in the striker role. The Jong Oranje failed to qualify for the 2004 tournament and Van Persie did not participate in the latter as he was already in the senior squad for the FIFA World Cup. He earned his first caps for the Netherlands in less than the span of a week, first in a 2–0 2006 FIFA World Cup qualifying win over Romania on 4 June 2005, and in another qualifier four days later against Finland, which saw him pick up his first international goal in a 4–0 victory.

After joining Arsenal in England, Van Persie settled in Hampstead, an affluent suburb of north London. Van Persie is married to Moroccan Bouchra (née Elbali) and the couple have two children, a son named Shaqueel born in 2006 and daughter Dina born in 2009. When asked if this caused him to convert to Islam, Van Persie said, “It’s not true. I am not a Muslim, nor a Christian or a Jew. I have been raised liberally. If you want to become a Muslim it should come from the heart. I would not do it just to please my wife. To believe for me is a quest for being a good man.”

Van Persie opened his 2008–09 account on 31 August with a brace in Arsenal’s 3–0 league victory over Newcastle United. On 29 October, he scored his fiftieth career Arsenal goal in a 4–4 home draw with North London derby rivals Tottenham, but was hit with his first red card of the season on 1 November after knocking down goalkeeper Thomas Sørensen with a shoulder charge in a 2–1 loss to Stoke City. Sørensen later admitted to “teasing” Van Persie in an attempt to provoke a reaction. On 30 November, he scored a brace against Chelsea to help Arsenal come from behind and pick up a 2–1 victory at Stamford Bridge. On 21 December 2008, he scored a spectacular goal against Liverpool, which was later named the second BBC Goal of the Month of his career. With captain Cesc Fàbregas injured and regular stand-in skipper Manuel Almunia rested, Van Persie captained Arsenal for the first time on 3 January 2009 for the club’s 3–1 FA Cup Third Round victory over Plymouth Argyle. Van Persie scored Arsenal’s first and third goals, while the second was a result of his cross being deflected into the net by a Plymouth player for an own goal.

In January 2009, every Arsenal goal that month was either scored or assisted by Van Persie, which earned him the club’s Player of the Month award. His most inspirational display being against Hull City, where he struck the post with a freekick, and provided three assists to his teammates; he later received the Man of the Match award. On 24 February, Van Persie scored a crucial penalty that earned Arsenal a 1–0 win over Roma in the UEFA Champions League Round of 16 encounter, after he was fouled by defender Philippe Mexès. He followed it up with a fifth Champions League goal by converting another penalty against Villarreal in a 3–0 victory.

With only one year remaining of his contract, Van Persie was in negotiations with Arsenal about an extension for several months in 2009. Finally, it was announced in July that he had signed a new long-term contract with his club, stating, “My heart is with Arsenal and I just can’t picture myself in a different shirt.” The departure of Emmanuel Adebayor also meant that the Dutchman was now the main striker in Wenger’s 4–3–3 system. Van Persie started the 2009–10 season with two assists in the first match against Everton, which led to a 6–1 victory. As one of the first choice penalty and corner takers, he has set up many of Arsenal’s goals, including Thomas Vermaelen’s debut goal against Everton. He scored his first goal of the season in the 4–2 loss at Eastlands to Manchester City, where he later had his head stomped on by former teammate Adebayor (an act the referee failed to notice, but the FA later charged Adebayor with violent conduct and served him with a three-game suspension).

In the 2010 World Cup qualifying process, the Netherlands graduated from Group 9 with a 100% record.

Van Persie was included in the preliminary squad for the 2010 FIFA World Cup in South Africa. On 27 May 2010, Netherlands manager Bert van Marwijk announced that he was in the final squad of 23 participating in the competition.

On 1 January 2011, van Persie scored his first goal of the season in a 3–0 away win over Birmingham City. On 15 January, he added two more goals to his tally in a comfortable 3–0 win over West Ham. This made him only the fourth Dutchman to reach 50 goals in England’s top division. Van Persie scored his first career hat-trick in a 3–0 win over Wigan Athletic on 22 January and two goals against Newcastle United in a 4–4 draw on 5 February. Continuing his fine form, he hit a brace the following week against Wolverhampton Wanderers scoring both Arsenal goals in a 2–0 win including a volley from inside the box. The ten goals he scored between 1 January and 12 February set a new Premier League record for most goals scored in the first two months of a calendar year.

Van Persie set the Emirates alight with a goal from an almost impossible angle in Arsenal’s fightback against Barcelona in the UEFA Champions League Round of 16, which ended 2–1 in favour of the Gunners. On 27 February 2011, Van Persie captained Arsenal at Wembley Stadium in the League Cup final, scoring the first half equalizer for the Gunners. It was his first goal at Wembley and his first in a cup final for Arsenal. However, he was later taken off in the second half with a knee injury he picked up while scoring the goal.

On 1 March 2011, he was ruled out for three weeks, which would see him miss the Champions League return leg with Barcelona. However, he recovered in time for the return leg at Camp Nou. During the game, he received a yellow card in the first half for a foul. In the second half, he was sent off after he received a second yellow card when the referee, Massimo Busacca, deemed him to be time-wasting by taking a shot at goal after the whistle was blown (one second earlier) for offside. Barcelona went on to score twice more and advanced to the quarter finals on a 4–3 aggregate result. Afterwards, Van Persie branded Busacca’s decision as a “total joke”, claiming that with the noise of the 95,000-strong crowd he could not hear the whistle. On 19 March 2011, he scored the equalizing goal in a 2–2 against West Bromwich Albion at The Hawthorns. The match finished 2–2 with Arsenal still five points behind the current leaders, Manchester United.

On 10 April 2011 in a match against Blackpool, Van Persie put in a Man of the Match performance to give Arsenal a crucial 3–1 win as he set up a goal and scored the third. On 24 April 2011, he became the first player to score in seven successive Premier League away games when he scored against Bolton, beating Didier Drogba’s record who was on six successive away games, between August and November 2009. However, the Gunners lost 2–1, all but ending their title hopes. On 1 May he assisted Aaron Ramsey who scored the winning goal against league leaders Manchester United to add a twist to the Premier League. Van Persie was named Premier League Player of the Month for April.

On 8 May 2011, Arsenal lost 3–1 against Stoke City at the Britannia Stadium. Van Persie scored the goal for Arsenal and extended his Premier League record by scoring in an eighth successive away match. In the last home game of the season, he scored against Aston Villa, but Arsenal lost the match 2–1. In the last game of the season away to Fulham, he managed to score in his ninth consecutive away match, bringing his goal tally for the season to a personal record of 18 league goals. He also equalled the record held by Cristiano Ronaldo and Thierry Henry by scoring 18 league goals from the turn of the year to the end of the season. He ended the season just two goals behind joint league top scorers, Carlos Tevez and Dimitar Berbatov in the race for the golden boot, despite being injured for half of the season. He was voted as the second best player of the 2010–11 season on Arsenal’s official website and also received the team’s Goal of the Season award for his audacious strike in the 2–1 victory over Barcelona in the Champions League.

Having been appointed vice-captain for the 2010–11 season, Van Persie was promoted to club captain following the transfer of Cesc Fàbregas to FC Barcelona at the start of the 2011–12 season. On 24 August, Van Persie scored his first goal of the 2011–12 season in the second leg of Arsenal’s 2–1 away victory against Udinese in a Champions League play off match. On 24 September 2011, he scored twice against Bolton Wanderers to raise his tally for Arsenal to 100 goals, becoming the 17th Arsenal player to reach this milestone.

On 16 October 2011, he scored the fastest goal of the 2011–12 Premier League season, 28 seconds into a home match against Sunderland. He went on to score a late winner from a curling left foot free kick, to put Arsenal 2–1 ahead. After the match, Van Persie stated his dedication to the club after speculation surrounding a future transfer away from the Emirates. On 23 October, he came on as a substitute in the 66th minute replacing Marouane Chamakh and scored two goals against Stoke City. The match ended 3–1 with another home win for Arsenal.

He then continued his scoring run for Arsenal on 29 October by scoring a hat-trick in Arsenal’s 5–3 victory against Chelsea at Stamford Bridge. Due to his consistent performances and good goal-scoring form, Van Persie was named the Premier League Player of the Month for October 2011. He continued scoring as he scored Arsenal’s opening goal of the match in their 3–0 win over West Bromwich Albion on 5 November along with two assists. After the international break, he scored both Arsenal goals against Norwich City to help the Gunners to a 2–1 win on 19 November 2011. In Van Persie’s fifth Champions League match of the season he scored twice in the 49th and 86th minute to lift Arsenal to a 2–1 victory over Borussia Dortmund and to qualify Arsenal for the knockout phase on 23 November 2011.

After failing to score against Fulham, Van Persie scored again for Arsenal, this time against Wigan Athletic to make the score 4–0 to Arsenal on 3 December 2011. He then added to his tally with the only goal of the game against Everton, an exquisite volley from an Alex Song long ball. The following match, versus Aston Villa, saw him score a penalty and provide an assist. Van Persie’s final goal of the 2011 calendar year came in Arsenal’s one-goal win over Queens Park Rangers on the last day of the year. The goal took his tally for the year to 35 goals, one short of Alan Shearer’s Premier League record.

On 2 September 2011, Van Persie scored four goals in a record breaking 11–0 victory in UEFA Euro 2012 qualifying Group E over San Marino. He entered the Dutch national team’s top 10 all-time topscorer ranking with a tally of 25 goals, dislodging Marco van Basten in the process. Van Persie had not scored four goals in a single match for a long while. Van Persie contributed six goals in total during qualifying.

With Arsenal in unpredictable form, Van Persie was again of supreme importance for Arsenal, this time in the North London derby against Tottenham Hotspur, played on 26 February. Arsenal went 2–0 down at half in the first half, but Van Persie equalised before half-time. In the second half, he gave the assist to Walcott’s goal as Arsenal performed a remarkable comeback to win the game 5–2. A week later, Van Persie scored both goals in a 2–1 away win at Liverpool, one being a left-footed volley assisted by Alex Song, similar to the goal he scored against Everton earlier in the campaign. On 11 April 2012, after scoring the penalty against Wolverhampton Wanderers in a 3–0 away win, he became only the second player, after Ian Wright, to score against 17 Premier League clubs in a 20-team campaign. He finished as the top goal-scorer in the Premier League with 30 goals, and became Arsenal’s 8th all-time top scorer with 132 goals.

On 4 July 2012, Van Persie announced that he would not be signing a new contract with Arsenal.

On 15 August 2012, Arsenal announced they had agreed terms with Manchester United for his transfer, but Van Persie had yet to agree personal terms with the club. On 17 August, Van Persie transferred to Manchester United for an initial £22.5 million, with an additional £1.5 million to follow if United won a Premier League or Champions League title within the next four years. He signed a four-year contract, keeping him at the club until June 2016. Van Persie chose the number 20 shirt after assistant coach Rene Meulensteen convinced him that he would help secure Manchester United’s 20th league title.

He made his debut on 20 August, coming on as a 68th-minute substitute for Danny Welbeck in a 1–0 loss to Everton. Five days later, with his first shot for the club, he scored his first Manchester United goal, United’s first in a 3–2 home victory over Fulham. On 2 September 2012, he scored his first hat-trick for United in another 3–2 victory over Southampton, helping pull United back from a 2–1 deficit; his third goal was his 100th in the Premier League. Van Persie netted a late penalty on 23 September to give United a 2–1 away win at Anfield against Liverpool, and opened his European account with the club, scoring a brace in the 2–1 away win against CFR Cluj, with both goals assisted by Wayne Rooney.

On 13 June 2012, Van Persie scored the Dutch goal in a 2–1 loss to Germany in the European Championship group stage. Having missed two earlier chances, he picked up the ball near the halfway line, turned and ran at the German defence, before firing into the bottom corner from the edge of the penalty area.

After scoring against Everton on 10 February 2013, Van Persie went ten games without scoring, finally ending his barren run when he scored a penalty against Stoke on 14 April. Against Queens Park Rangers on 23 February, he had to be substituted after falling against a television camera and injuring a hip, but was fit for United’s next match.

Van Persie ended the 2014 FIFA World Cup qualification campaign as top scorer in the UEFA section with 11 goals. In June 2013, he was appointed captain of the Dutch national team by manager Louis van Gaal. On 11 October 2013, he became the Netherlands’ top goalscorer of all-time in an 8–1 defeat of Hungary, the Dutch’s penultimate Group D match, where he scored a hat-trick. This put him on 41 goals in 80 internationals, surpassing the record previously held by Patrick Kluivert.

Van Persie has a sponsorship deal with German sportswear and equipment supplier, Adidas. Having previously worn Adidas Predator football boots he made the transition to the Adidas F50 adiZero boots in 2013.

Van Persie kick-started his new campaign by scoring both of Manchester United’s goals in their 2–0 win against Wigan Athletic in the Community Shield, securing David Moyes’ first honour as club manager. He scored twice more in the first Premier League match of the season, against Swansea City, for the first of which “he chested it down and executed a crisp, instant scissor-kick into the net”. On 19 March 2014, Van Persie scored a hat-trick in a 3–0 win over Olympiacos in the second leg of the Champions League second round to send United through to the quarter-finals 3–2 on aggregate.

Van Persie scored his first goal for the season in his fourth league appearance in a 5–3 defeat to Leicester City on 21 September 2014. He scored again in the next game against West Ham United, helping United win the game 2–1. On 26 October 2014, against Chelsea, Van Persie scored a late equaliser to earn a point for United. In the dying minutes of injury time, Marouane Fellaini’s header from Ángel Di María’s free-kick was saved by Thibaut Courtois, and Van Persie smashed in the rebound to equalise. Van Persie celebrated the goal by taking his shirt off and was booked for his actions. His goal celebration was also labelled “stupid” by United coach Louis van Gaal.

On 11 January 2015, he suffered an ankle injury in a 1–0 home defeat to Southampton. Following Manchester United’s defeat to West Bromwich Albion, which saw Van Persie miss a penalty, he was stripped of his penalty-taking duties by Van Gaal.

On 14 July 2015, Van Persie joined Turkish side Fenerbahçe on a three-year deal for a fee claimed by Fenerbahçe to be £3.84 million. He was assigned the number 10 shirt. He and his former United teammate Nani debuted two weeks later in a goalless home draw against Shakhtar Donetsk in the third qualifying round of the season’s Champions League, with Van Persie a 68th-minute substitute for Moussa Sow. His league debut came on 14 August as a 60th-minute substitute for Fernandão in a 2–0 win at Eskişehirspor. Six days later, he scored his first goal for his new club: as a late substitute for Sow, he headed the only goal away to Atromitos Athens in the first leg of the Europa League play-offs, with his first of only two touches in the entire match. Van Persie scored his first domestic goal for the club on his first start on 23 August, finishing Nani’s pass for the opening goal in a 1–1 draw at Çaykur Rizespor.

On 28 August 2015, Van Persie was replaced by Arjen Robben as captain of the national team. He replaced Huntelaar for the final three minutes of a 2–1 away win over Kazakhstan in UEFA Euro 2016 qualifying on 10 October, his 100th appearance for the Netherlands. In doing so, Van Persie became the eighth Dutchman to reach the milestone. Three days later, in their final group game, Van Persie came on as a 38th-minute substitute for Jaïro Riedewald away to the Czech Republic and scored an own goal which handed the Czechs victory, despite scoring later on in a 3–2 defeat. The result meant that the Dutch did not qualify for an international tournament for the first time since 2002.

On 19 January 2018, Van Persie agreed to return to Feyenoord after cancelling his contract with Fenerbahçe. On 28 February, van Persie scored his 300th career goal in a victory that put Feyenoord into the 2017–18 KNVB Cup final. He also scored in the final later on 22 April as Feyenoord defeated 3–0 AZ Alkmaar to claim their 13th trophy.

In October 2018 he announced he would retire from football at the end of the 2018–19 season. On 3 March 2019 he scored his first hat-trick in the Eredivisie in a 4–0 win against FC Emmen.

On 12 May 2019, Van Persie played his last professional match as a footballer in a 2–0 home defeat against ADO Den Haag. He nearly played the entire match before being replaced by Dylan Vente in the 93rd minute of extra time. Feyenoord coach Giovanni van Bronckhorst had previously confirmed that this would be Van Persie’s last match despite having one matchday left in that season’s Eredivisie.

In June 2019, Vivianne Miedema moved ahead of Manon Melis as the Netherlands women’s national football team top goalscorer. Van Persie praised her achievement of 60 goals in 77 caps and readily acknowledged that he languished at third place in the overall list of Netherlands national team top goalscorers.

In May 2020, a year after his retirement, Van Persie became an assistant-coach to Dick Advocaat at his former club Feyenoord. He became the coach to the forwards of the team, working with former teammate Nicolai Jørgensen and talent Róbert Boženík amongst others.