On 9 March 2004, Gómez played ten minutes for Stuttgart in the Champions League first knock-out round against Chelsea and made his debut in the Bundesliga on 8 May, coming on for Imre Szabics in a 2–1 loss to Hamburger SV. These ended up as his only two appearances for the first team during the 2003–04 season. He would go on to make eight league appearances, one DFB-Pokal appearance, and one UEFA Cup appearance.

In the 2005–06 season, Gómez joined the first team permanently. He played 30 times in the Bundesliga, scoring six times at this level. His first goal came on 17 September 2005, the winner in a 2–1 defeat of Mainz 05. Gómez also played five times in the UEFA Cup, scoring twice, and played three times in both the DFB-Pokal, and DFL-Ligapokal.

In the 2006–07 season, Gómez established himself as one of the top scorers in the Bundesliga. However, he broke his hand on 10 March 2007 and suffered a torn ligament in his left knee. He made his comeback on 12 May 2007 and immediately scored after coming on from the bench. In that match, Stuttgart defeated VfL Bochum (3–2) and went two points clear heading into the Bundesliga’s final weekend, where they won at home against Energie Cottbus, thus becoming German champions. Further, Stuttgart also reached final of the DFB-Pokal, where Gómez participated, but Stuttgart lost to 1. FC Nürnberg. He finished the season with 14 goals in 25 league appearances and two goals in five DFB-Pokal appearances. After the season, he was named German Footballer of the Year for 2007 and extended his contract at Stuttgart until 2012.

Gómez has both German and Spanish citizenship, but played for all German youth national teams from age 14. He made his debut for the Germany senior team against Switzerland on 7 February 2007 in Düsseldorf. Germany won the match 3–1, with Gómez scoring Germany’s second goal. Gómez gained his second cap for Germany, coming on as a substitute for Kevin Kurányi in a UEFA Euro 2008 qualifier against San Marino, scoring two goals that contributed to a final 6–0 victory.

In the 2007–08 season, while the rest of his team struggled to keep performing at their 2006–07 season standards, Gómez remained at an astonishingly high level, scoring 19 goals in 25 appearances, second in the Bundesliga’s top scorer list, just behind Bayern Munich’s Luca Toni, who scored 24 times. In the DFB-Pokal, Gómez was the top scorer with six goals. Because of his development, many big clubs became interested in the then-23-year-old forward. Gómez gained the nickname “Mr. Zuverlässig” (“Mr. Reliable”), as seen in his second of three goals against Bundesliga rival Werder Bremen (final score 6–3), where he managed to net in a virtually unreachable pass by teammate Yıldıray Baştürk. On 9 May 2009, Gómez hit four goals to inspire Stuttgart to a 4–1 victory over Bundesliga champions VfL Wolfsburg. He also had six goals in three DFB-Pokal appearances and three goals in four UEFA Champions League appearances.

On 26 May 2009, Gómez eventually transferred to Bayern Munich for a Bundesliga record transfer fee, signing a four-year contract. The amount of the transfer fee varies from €30–35 million, depending on different sources. Gómez was not scoring like his usual self in his first season for Bayern, with just ten league goals and one Champions League goal netted, but in the DFB-Pokal, he was more prolific, with three goals in just four matches. Gómez was also short in the assists column, as well. Quite surprisingly, he made an impact as he was to start the majority of matches next season for Bayern. Also in his first season, Gómez was teamed up with his German international strike partner Miroslav Klose to give him some first-team experience.

In a friendly match against the United Arab Emirates played on 2 June 2009, Gómez scored four goals, ending his 15-game goal drought for the national team, in Germany’s 7–2 victory.

After an erratic first season at Bayern with 10 goals in 29 league appearances, Gómez established himself as a starter during the 2010–11 season (to an extent at the expense of Miroslav Klose and due to an injury sustained by Ivica Olić) and finished as top goalscorer in the Bundesliga with 28 goals. He scored his 100th Bundesliga goal with his third strike in a 1–8 away victory over FC St. Pauli on 7 May 2011, the hat-trick already being his fifth in the Bundesliga in the 2010–11 season, and his sixth overall, adding in his hat-trick against CFR Cluj in the Champions League. Gómez has scored 13 hat-tricks in his Bundesliga career, three with VfB Stuttgart and ten with Bayern. Gómez also netted eight times in the Champions League and finished in second place in the season’s top scorers, tied with Samuel Eto’o, although Bayern was eliminated in the round of 16 by Inter Milan. Gómez in all competitions scored 39 goals in his second season with the Bavarian club.

Gómez started the 2011–12 season in similar style towards the previous season and he opened his league account on 20 August 2011 in Bayern’s thrashing of Hamburger SV. Seven days later, Gómez scored a hat-trick away to 1. FC Kaiserslautern. On 10 September, Gómez scored four goals in Bayern’s 7–0 rout of SC Freiburg, sealing four-straight wins for the Bavarians and a return to the top of the Bundesliga table. On 27 September, Gómez scored two first-half goals as Bayern defeated Manchester City 2–0 in the group stage of the Champions League.

Gómez scored his second brace of the Bundesliga campaign against Hertha BSC when Bayern won 4–0. Gómez then recorded another brace on 29 October when Bayern then defeated 1. FC Nürnberg 4–0. Then, on 11 December 2011, he scored his third brace of the season and sealed Bayern’s 2–1 win over southern rivals VfB Stuttgart, his former club. On 2 November 2011, he scored a hat-trick in a Champions League group stage match against Napoli. Bayern went on to win 3–2. In the DFB-Pokal, Gómez scored just two goals. On 16 December 2011, Gómez scored his 50th goal for the calendar year of 2011, against 1. FC Köln.

On 13 March 2012, the second leg of their Champions League tie against Basel, Bayern Munich overturned their 0–1 away loss as Gómez netted four of Bayern’s seven goals, firing the Bavarians through to the quarter-finals 7–1 on aggregate. In the quarter-finals, Bayern faced French Ligue 1 side Olympique de Marseille and in the first leg on 28 March, Gómez fired in his 11th Champions League goal of the campaign in a 2–0 win for the Bavarians.

On 4 April, Gómez signed a new contract with Bayern Munich, keeping him at the club until the summer of 2016. Gómez scored the winning goal in Bayern’s 2–1 victory over Real Madrid in the first leg of their semi-final clash. Bayern went on to win the tie 3–1 on penalties after the teams were deadlocked 3–3 on aggregate. On 19 May 2012, he played in the Champions League Final against Chelsea. He failed to find the net in regular time in the game but scored in the penalty shoot-out as Bayern once again fell at the final hurdle, losing 4–3 on penalties after a 1–1 finish. He finished the 2011–12 season with 26 goals in 33 league appearances, two goals in five DFB-Pokal appearances, and 13 goals in 14 Champions League appearances.

Gómez returned to action on 20 November 2012 in the club’s 1–1 draw with Valencia in the group stage of the Champions League, coming on as a 79th minute sub for winger Franck Ribéry. The striker scored his first goal within a minute of his Bundesliga season debut, slotting home after good work from Toni Kroos, capping off a 5–0 victory over Hannover 96 on 24 November. On 5 December, Gómez opened the scoring for the hosts in their final group game of the Champions League, a 4–1 defeat of BATE Borisov which secured the Bavarians top spot in the group over Valencia.

Gómez ended his nine-year relationship with Silvia Meichel on 2 October 2012. Gómez began dating German model Carina Wanzung in December 2012. They married on 22 July 2016.

Following the winter break, Gómez pushed for a first-team berth, scoring two goals and setting up another as Bayern cruised past Werder Bremen 6–1 on 23 February 2013. The game was coincidentally his manager Jupp Heynckes’ 1,000th game as a player and coach in the Bundesliga. The striker was a used substitute against Eintracht Frankfurt on 6 April, as a lone Bastian Schweinsteiger strike confirmed an 11th successive victory and a 23rd national title for the club, Gómez’s second with Bayern and third overall.

On 6 June 2013, Gómez’ consultant Uli Ferber announced that it “is quite clear that he will separate from Bayern” as he had fallen behind Mario Mandžukić in the pecking order for starting striker.

On 8 July 2013, Gómez joined Serie A side Fiorentina by signing a four-year deal, for a fee believed to be around €20 million. He was officially unveiled as a Fiorentina player on 15 July, to a crowd of 20,000 people.

Gómez scored his first two goals for la Viola in a 5–2 defeat of Genoa on 1 September. In the following match, a 1–1 draw with Cagliari, Gómez sustained an injury which kept him out of the team until Fiorentina’s match against Internazionale on 15 February 2014.

Gómez was excluded from national team squad for UEFA Euro 2016 qualifying Group D encounters against Ireland and Georgia. His performance at first half of 2015–16 Süper Lig lead Gómez to be recalled to national team, for the first time after the international friendly held against Argentina on 4 September 2014, that he was recalled to the Germany squad for friendlies against France and the Netherlands in November 2015. He scored his first international goal in four years in a 2–3 loss to England in Berlin on 26 March 2016.

Gómez scored twice in Fiorentina’s 3–1 win over Atalanta in the last 16 of the Coppa Italia on 21 January 2015, and followed this up with another brace 13 days later in a 2–0 quarter-final win away to Roma. He finished 2014–15 season with 4 goals in 20 league appearances, four goals in four Coppa Italia appearances and two goals in eight Europa League appearances.

On 30 July 2015, Gómez joined Beşiktaş on a season long loan contract from Fiorentina for 2015–16 Süper Lig, with a buy option. The contract consisted €3.50 million of seasonal wage. He successfully completed a medical test on 31 July 2015. Gómez officially signed in the club along with 4 other new players, including his compatriot Andreas Beck, at a press conference held on 7 August 2015. He chose number 33 for his shirt.

Substituted on Oğuzhan Özyakup at 73rd minute, Mario Gómez had his Süper Lig debut on 16 August 2015 at week 1 encounter against Mersin İdman Yurdu at Mersin Arena which ended 5–2 in favour of Beşiktaş. Gómez secured all two goals of week 4 game in which Beşiktaş beat Medipol Başakşehir at Atatürk Olympic Stadium on 13 September 2015. On 21 September 2015, at week 5 game against Gençlerbirliği, Gómez reportedly escaped a red card narrowly although an alleged deliberate elbow on Icelandic midfielder Ólafur Ingi Skúlason at 55th minute. On 27 September 2015, played at Atatürk Olympic Stadium, Gómez scored 1st and 3rd goals of Beşiktaş at derby game against Fenerbahçe where game ended 3–2 in favour of Beşiktaş and helped the team to top Süper Lig standings.

Gómez scored twice and secured victory for Beşiktaş at week 7 game against Eskişehirspor at New Eskişehir Stadium, that ended 2–1 on 4 October 2015. By end of week 7 of Süper Lig, scoring 6 goals at that stage, Gómez reached 50% shoot accuracy stats, sending 6 accurate shots of total 12. Gómez scored the equaliser at week 3 of Group H game against Lokomotiv Moscow, ended 1–1 at Lokomotiv Stadium, Moscow, on 22 October 2015. On 26 October 2015, Gómez scored 3rd goal against Antalyaspor at New Antalya Stadium, at week 9 game ended 5–1 for Beşiktaş.

At week 12 game against Sivasspor in Istanbul, Gómez scored first goal of game on 44th minute via penalty kick where Beşiktaş beat their opponent 2–0, on 22 November 2015.

On 5 December 2016, Gómez opened scoreboard on 12th minute, following assist of José Sosa at week 14 encounter against Kayserispor, ended 2–1 for Beşiktaş at Kadir Has Stadium, Kayseri. On 10 December 2015, Gómez scored the only goal of Beşiktaş against Sporting at Europa League Group Stage week 6 encounter ended 3–1 for Portuguese side at Estádio José Alvalade, where Beşiktaş eventually were eliminated from the competition. On 14 December 2015, Gómez scored first goal of Beşiktaş by a diving header in derby game against Galatasaray that ended 2–1 for Beşiktaş at Atatürk Olympic Stadium. At week 16, Gómez opened scoring tally of Beşiktaş while they were 2–0 down against Osmanlıspor, which eventually ended 3–2 in favour of Beşiktaş at Osmanlı Stadium in Ankara, on 21 December 2015. On 28 December 2015, Gómez scored 2nd goal of week 17 encounter against Konyaspor that ended 4–0 at Başakşehir Fatih Terim Stadium. Being top scorer 13 goals along with Samuel Eto’o, Gómez completed first half of the season with highest shooting accuracy, providing 29 shoots on target. He also scored 2 goals at UEFA Europa League until the end of 2015.

In Süper Lig week 20 game against Gaziantepspor, Gómez scored twice on 61st and 70th minutes when Beşiktaş achieved a comfortable 4–0 win on 7 February 2016. Scoring on 64th minute, Gómez had the only goal scored on week 22 game against Gençlerbirliği and secured the 1–0 win for Beşiktaş, on 26 February 2016. Gómez scored twice against Eskişehirspor at week 24 game on 7 March 2016, which ended 3–1 for Beşiktaş. His tally lead him to reach 19 Süper Lig goals and thus equilsed the “most scoring foreign player in single Süper Lig season” record of Beşiktaş, along with Pascal Nouma and Demba Ba.

Beşiktaş and Trabzonspor faced each other on rescheduled week 19 game on 14 March 2016, in which Gómez scored the first goal of the two, on 76th minute, finally ended 2–0 in favour of Beşiktaş. Gómez was the scorer of the first goal ever scored on newly built Vodafone Park, on 22nd minute of week 28 encounter against Bursaspor of 2015–16 season, ended 3–2 as well as the first ever win of the hosting side Beşiktaş at this stadium, on 11 April 2016. This was his 21st goal of 2015–16 season.

In May 2016, Gómez continued to produce goals. He scored once more at Istanbul derby versus Galatasaray at 76th minute which sealed the final score of 1–0 for Beşiktaş at Türk Telekom Stadium, on 8 May 2016 at week 32. 15 May 2016, at match week 33, scoring in fifth consecutive Süper Lig games, Gómez converted another strike and remaked his last Süper Lig goal of the season against Osmanlıspor on 48th minute, the latter of 3 goals scored by Beşiktaş as the score of 3–1. Thus, producing the 28th goal in all competitions, Gómez became the “most scoring foreign player across all competitions in single season”, beating previous record of Demba Ba with 27 goals scored 2014–15 season.

Gómez scored total of 26 goals at 2015–16 Süper Lig season and became top scorer ahead of Samuel Eto’o and Hugo Rodallega. He completed the season with 28 goals in 41 games played in all competitions. On 20 July 2016, Gómez announced his farewell message via his Facebook account that he will not continue to play for Beşiktaş following a personally described “difficult decision” on a political basis, which was perceived as a reference to 2016 coup d’état attempt in country.

On 17 August 2016, Gómez returned to the Bundesliga to sign for VfL Wolfsburg. He scored his first goal for the club on 22 October, netting in a 3–1 defeat to Darmstadt 98. His goal was the 1,000th scored by Wolfsburg in the Bundesliga. On 2 April 2017, Gómez scored his first hat-trick for the club, netting three times in seven minutes as Wolfsburg came from 2–0 down to draw 3–3 with Bayer Leverkusen. His third on the night was his 150th goal scored in the Bundesliga. He ultimately scored 16 league goals for the season as Wolfsburg narrowly avoided relegation via the relegation play-offs. He finished the 2016–17 season with 18 goals in 37 appearances in all competitions.

On 21 June 2016, Gómez was selected to start in Germany’s final Euro 2016 group match against Northern Ireland, scoring the winning goal in the 30th minute. On 26 June 2016, Gómez scored in the 43rd minute in Germany’s Round of 16 3–0 win against Slovakia, becoming Germany’s all-time leading scorer at the UEFA European Championship with five goals.

After keeping his team in the top flight, Gómez signed a new contract in June 2017. In August, manager Andries Jonker named him as captain, succeeding Diego Benaglio. In his final half-season at the Volkswagen Arena, Gómez scored only once in 15 appearances.

On 22 December 2017, it was announced that Gómez will return to VfB Stuttgart on 1 January 2018. The fee was undisclosed. He signed a contract until June 2020. He finished the 2017–18 season with Stuttgart eight goals in 16 appearances.

On 4 June 2018, Gómez was selected in Joachim Löw’s final 23-man squad for the 2018 FIFA World Cup. He made his appearance in the 79th minute by coming in for Marvin Plattenhardt during their opening match against Mexico, but the game ended 1–0 loss for Germany. On 24 June, Gómez provided an assist to Marco Reus’ equalizing goal with his first touch of the match after coming on as a substitute in the second half in a 2–1 victory over Sweden during the second group stage match. On 5 August, he announced his retirement from international football.

On 28 June 2020, Stuttgart announced that Gómez had ended his professional career, after scoring in his final match for the club and helping them secure promotion back to the Bundesliga.