De Bruyne began his career with hometown club KVV Drongen in 1997. Two years later, he joined Gent and moved to Genk in 2005. De Bruyne continued his development in their youth set-up and was rewarded for his progress by being promoted to the first team squad in 2008.

De Bruyne made his first team debut for Genk in a 3–0 defeat at Charleroi on 9 May 2009. Having established himself in the team the following season, on 7 February 2010, De Bruyne scored his first goal for the club, which secured all three points for Genk in a 1–0 win against Standard Liège. He scored five goals and made 16 assists in 32 league matches during the 2010–11 season as Genk were crowned Belgian champions for the third time. On 29 October 2011, De Bruyne scored his first hat-trick for Genk against Club Brugge, which ended in a 5–4 win for Genk. On 28 January 2012, De Bruyne scored a brace against OH Leuven in a 5–0 win. On 18 February 2012, De Bruyne scored his first goal back at Genk following his agreed transfer to Chelsea and also assisted the other goal in a 1–2 away win against Mons. De Bruyne ended the season by wrapping up the scoring in a 3–1 victory over Gent. He finished the league campaign with eight goals from 28 appearances.

De Bruyne was capped by Belgium at under-18, under-19, and under-21 level. He made his debut for the Belgian senior team on 11 August 2010 in an international friendly against Finland in Turku; the game ended in a 1–0 loss for Belgium.

On 31 January 2012, on the winter transfer deadline day, Premier League club Chelsea and Genk announced the permanent signing of De Bruyne, with the fee rumoured to be in the region of £7 million. He signed a five-and-a-half-year contract at Stamford Bridge, but would stay at Genk for the remainder of the 2011–12 season. De Bruyne told the club website, “To come to a team like Chelsea is a dream but now I have to work hard to achieve the level that’s necessary.” On 18 July 2012, De Bruyne made his debut for Chelsea in a friendly match against Major League Soccer (MLS) side Seattle Sounders FC in a 4–2 win. De Bruyne also played the first half against Ligue 1 giants Paris Saint-Germain at Yankee Stadium, New York.

On 31 July 2012, Chelsea announced that De Bruyne was to join Werder Bremen in the Bundesliga on a season-long loan deal. He scored his first goal for Bremen in a 3–2 defeat to Hannover 96 on 15 September, netting from 11 yards out after being played in by Eljero Elia. He continued his good form, scoring in Bremen’s next game, a 2–2 draw with VfB Stuttgart, on 23 September. De Bruyne got back on the score sheet on 18 November, scoring the winning goal — despite his team being down to 10 men — as Bremen came from a goal down to defeat Fortuna Düsseldorf 2–1.

De Bruyne scored his first goal in over two months on 4 May 2013, since netting a consolation goal in Bayern Munich’s 6–1 hammering of Bremen, putting his side up 2–0 at home to TSG 1899 Hoffenheim before a late brace from Sven Schipplock meant that the game finished 2–2. He followed this up with a goal in Bremen’s next match, securing a place in the Bundesliga for the next season with a 1–1 draw against Eintracht Frankfurt on 11 May.

After a successful loan spell in the Bundesliga with Werder Bremen, De Bruyne was linked with a move to stay in Germany with either Borussia Dortmund or Bayer Leverkusen. Incoming manager José Mourinho, however, assured De Bruyne he was a part of Chelsea’s plan for the future, and the player officially returned to Chelsea on 1 July 2013.

On 18 January 2014, Wolfsburg signed De Bruyne for a fee of £18 million (€22 million). On 25 January 2014, he made his debut for Wolfsburg in a 3–1 home loss against Hannover 96. On 12 April 2014, De Bruyne assisted 2 goals in their 4–1 home win against 1. FC Nürnberg. After a week he scored his first goal for Wolfsburg in 3–1 away win against Hamburger SV. He also scored in the last two matches of the Bundesliga helping his team to win against VfB Stuttgart and Borussia Mönchengladbach.

De Bruyne scored his first goal of the 2014–15 season on 2 October 2014, volleying in a clearance from outside the box to salvage a 1–1 draw against Lille in the Europa League. In the third group match away to Krasnodar on 23 October, De Bruyne scored twice as Wolfsburg secured their first win in the competition with a 4–2 victory. On 30 January 2015, he scored another brace in a 4–1 home win against Bayern Munich, their first Bundesliga defeat since April 2014. On 1 March 2015, De Bruyne assisted three goals in a 5–3 win over his former club Werder Bremen.

On 13 May 2014, he was named in Belgium’s squad for the 2014 FIFA World Cup. In their first game of the tournament, against Algeria in Belo Horizonte, De Bruyne assisted Marouane Fellaini’s equaliser and was named man of the match by FIFA. In the round of 16, De Bruyne scored Belgium’s opening goal in the third minute of extra time as they defeated the United States 2–1.

On 10 October 2014, De Bruyne scored twice in a 6–0 rout of Andorra in UEFA Euro 2016 qualifying, equaling the team’s record victory in a European qualifier set in 1986. On 3 September 2015, De Bruyne scored in a 3–1 win over Bosnia and Herzegovina. On 10 October 2015, De Bruyne scored in a 4–1 win over Andorra, which secured Belgium’s place at the UEFA Euro 2016 finals. Three days later, he scored in a 3–1 win over Israel, securing Belgium top-spot in the group. On 31 May 2016, De Bruyne was selected for Belgium’s final 23-man squad for UEFA Euro 2016. On 18 June 2016, De Bruyne was praised for his performance in Belgium’s 3–0 win over the Republic of Ireland. On 26 June 2016, De Bruyne was voted BBC Man of the Match for his performance in a 4–0 win over Hungary in the round of sixteen, where he provided two assists.

Since 2014, De Bruyne has been in a relationship with Michèle Lacroix, who announced on 28 September 2015 that she was pregnant with the couple’s son. Mason Milian De Bruyne was born on 10 March 2016. Their second son, Rome De Bruyne, was born on 31 October 2018. De Bruyne and Lacroix married in June 2017. In April 2020, it was announced that they were expecting their third child, who was later born in September 2020, to be their first daughter named Suri.

His autobiography, entitled Keep It Simple, was published by Borgerhoff & Lamberigts in October 2014.

On 12 March 2015, De Bruyne scored two goals in a 3–1 first leg Europa League round of 16 victory over Internazionale. On 15 March 2015, he scored one goal and assisted another two in 3–0 victory over SC Freiburg.

De Bruyne ended the league season with 10 goals and 21 assists, the latter a new Bundesliga record, as Wolfsburg finished second in the Bundesliga and qualified for the 2015–16 UEFA Champions League. On 30 May 2015, he started and scored in the 2015 DFB-Pokal Final as Die Wölfe defeated Borussia Dortmund 3–1 at the Olympiastadion in Berlin.

De Bruyne began the season by winning the 2015 DFL-Supercup against Bayern Munich, providing the cross for Nicklas Bendtner’s 89th-minute equaliser for a 1–1 draw and then scoring in the subsequent penalty shootout. On 8 August 2015, he continued his good form by scoring his first goal of the season, and providing two assists in a 4–1 win at Stuttgarter Kickers in the first round of the DFB-Pokal.

On 30 August 2015, Manchester City announced the arrival of De Bruyne on a six-year contract, for a reported club-record fee of £55 million (€75 million), making him the second most expensive transfer in British football history after Ángel Di María’s move to Manchester United in 2014. He made his debut for the team in the Premier League on 12 September against Crystal Palace, replacing injured Sergio Agüero in the 25th minute. On 19 September, he scored his first goal for the club against West Ham United in first half stoppage time in an eventual 2–1 loss. He went on to score in a 4–1 League Cup win against Sunderland, on 22 September and a 4–1 loss to Tottenham Hotspur in the Premier League on 26 September. On 3 October, he scored in the team’s 6–1 win against Newcastle United.

On 27 January 2016, De Bruyne scored a goal in a League Cup semi-final 3–1 victory over Everton, but sustained an injury to his right knee that would keep him out of the team for two months. On 2 April, De Bruyne made his return from injury in a 4–0 win against Bournemouth at Dean Court, scoring the team’s second goal in the twelfth minute. Four days later, he scored the opening goal in a 2–2 draw with Paris Saint-Germain in the UEFA Champions League quarter-final first-leg at the Parc des Princes. On 12 April, De Bruyne scored the winning goal against Paris Saint-Germain, advancing Manchester City to the Champions League semi-finals, for the first time in the club’s history, on an aggregate score of 3–2. Writing in The Independent, Mark Ogden said, “It was a stunning goal from the Belgian, who took a touch to control the ball before curling it beyond Kevin Trapp from the edge of the penalty area.” De Bruyne’s next goal came on 8 May 2016 in a 2–2 draw with Arsenal, although the result left City’s Champions League qualification hopes out of their own hands.

On 10 September 2016, De Bruyne scored and assisted in the first Manchester derby of the season which City won 2–1 and was awarded the Man of the Match. On 17 September 2016, De Bruyne was awarded the Man of the Match, in a 4–0 win over Bournemouth. De Bruyne scored the first, assisted the fourth, and provided key passes on both the second and third goals. After the international break, Manchester City drew their next game, against Everton, played on 15 October 2016 with the scoreline finishing at 1–1. Agüero and De Bruyne both missed their penalties while Nolito came off the bench to equalise for City. On 1 November, De Bruyne scored from a free kick in the team’s 3–1 win over FC Barcelona. On 21 January 2017, De Bruyne was involved in both of City’s goals, as he netted once himself and also assisted Leroy Sané’s, in a 2–2 home draw with Tottenham Hotspur; he was subsequently named Man of the Match. On 19 March 2017, De Bruyne displayed an excellent performance in a 1–1 draw against Liverpool at the Etihad Stadium, where he set up a goal for Agüero.

De Bruyne set up both Agüero’s and Gabriel Jesus’ goals, on 9 September 2017, in a 5–0 home victory over Liverpool. On 16 September, De Bruyne assisted Agüero for his first goal in an eventual 6–0 win over Watford. On 26 September, De Bruyne scored his first goal of the 2017–18 season in a 2–0 win over Shakhtar Donetsk. On 30 September 2017, he scored his first goal of the 2017–18 Premier League season, as City beat his former club Chelsea with a 1–0 scoreline at Stamford Bridge. On 14 October, De Bruyne provided two assists in a 7–2 win over Stoke City. On 5 November, De Bruyne scored in a 3–1 win over Arsenal. On 18 November, he scored in a 2–0 away win over Leicester City. On 29 November, he scored City’s opener and assisted Sterling’s last-minute winner in a 2–1 win over Southampton.

Although he is not blessed with significant physical strength, pace, or ability in the air, he is a quick and elegant player on the ball, with good dribbling skills, while his positional sense, tactical intelligence, movement, direct style of play, and ability to run at defences when in possession also enable him to take advantage of spaces in the opposition’s defence, and subsequently create chances and goalscoring opportunities for himself or his teammates, making him a dangerous offensive threat on counter-attacks. In addition to his creative abilities, he is also capable of scoring goals by making late runs off the ball from behind into the penalty area, and is an accurate set-piece taker. De Bruyne was ranked the fourth-best footballer in the world by The Guardian in 2017 and the twelfth-best in 2019.

On 22 January 2018, De Bruyne signed a new long-term contract with the club, keeping him at the club until 2023. On 23 January, he scored the winning goal in a 3–2 win over Bristol City in the EFL Cup semi-final second leg, which helped City advance to the final, having won the tie by an aggregate scoreline of 5–3. On 31 January, he scored and assisted in a 3–0 win over West Bromwich Albion, and was voted BBC Man of the Match. On 10 February, he provided three assists, two for Sergio Agüero and one for Raheem Sterling, in a 5–1 win over Leicester City, taking his assists tally to 14. On 25 February, he started in the 2018 EFL Cup Final against Arsenal, and played the whole 90 minutes, with Manchester City winning 3–0 to obtain their first piece of silverware of the 2017–18 season, and their first trophy overall under Pep Guardiola.

On 31 March 2018, he provided an assist for Gabriel Jesus in a 3–1 win over Everton, ensuring that City would require only one more win to secure the Premier League title. On 22 April, he scored in a 5–0 win over Swansea City. On 13 May, on the final day of the season, De Bruyne assisted Gabriel Jesus’ winning goal in a 1–0 win over Southampton, which took champions City’s total points tally to 100. De Bruyne was also voted as BBC Man of the Match. For his 16 assists registered across the league season, De Bruyne won the inaugural Premier League Playmaker of the Season award. He was also selected in the PFA Team of the Year, and was also voted as Manchester City Player of the Season.

On 15 August 2018, De Bruyne suffered a knee injury during a training session, with several news websites reporting that he could potentially not play for up to three months. Two days later, Manchester City confirmed that he had suffered a lesion of the lateral collateral ligament in his right knee, with no surgery required, and that he was expected to not play for three months. Soon after De Bruyne returned to action in October 2018, he once again suffered a knee ligament injury in the 4th round of the EFL Cup against Fulham. The injury was expected to keep him out for 5–6 weeks but he resumed full training much earlier than expected after only 3 weeks out. He came on as substitute in the FA Cup final against Watford, scoring the third goal and assisting two more, as City won the first-ever domestic treble in English men’s football. His performances meant he was named Man of the Match.

On 15 December 2019 De Bruyne scored a brace in a 3–0 Premier League win over Arsenal at the Emirates.

De Bruyne scored his 50th City goal in all competitions on 26 February 2020 in their 2–1 victory, coming from behind, over Real Madrid in their Champions League Round of 16 clash.

On 21 September 2020, De Bruyne scored and assisted in a 3–1 away win over Wolves in City’s first game of the season.