On 10 November 2007, Fabián made his first-team debut in a league match against Jaguares de Chiapas in the Apertura 2007 season under coach Efrain Flores, coming in as a substitute for Sergio Ávila in the 85th minute of the match. Fabián scored his first goal for Guadalajara in his second appearance, on 2 February 2008, in a 6–0 win over Morelia.

Fabián was selected by coach Juan Carlos Chávez to participate in the 2009 CONCACAF U-20 Championship held in Trinidad and Tobago. He made his youth International debut 7 March 2009 against Costa Rica wearing the number 8 shirt. Fabián managed three appearances for Mexico during the tournament; Mexico placed last in their group, thus failing to qualify to the 2009 FIFA U-20 World Cup.

In the 2010 Copa Libertadores Finals, Fabián scored the first goal in a 3–2 defeat against Internacional.

On 15 October 2011, he scored the first hat-trick of his career against Estudiantes Tecos; Guadalajara went on to win the match 5–2.

In 2011, Marco was called up by Luis Fernando Tena to form part of the “unofficial national team” composed entirely of players under the age of 22 to compete in the 2011 Copa América. He started most of the preparation games and scored a few goals before being suspended for six months, along with seven more players, for breaking disciplinary codes at their concentration hotel in Quito.

In early 2012, Fabián was called up by coach Luis Fernando Tena to participate in the 2012 Olympic Qualifying Tournament. He made his debut 23 March 2012 against Trinidad and Tobago, scoring a hat-trick in a 7–1 win for Mexico. Fabián also went on to score in the semi-final match against Canada, winning the match 3–1. He then score from a long-range shot in the final match against Honduras, winning the match 2–1 and also the tournament, thus qualifying Mexico for the 2012 Summer Olympics. He finished the tournament as top goal scorer alongside his teammate Alan Pulido with five goals in five appearances.

Fabián made the final list for those players participating in the 2012 London Olympics. He made his debut in Mexico’s first match of the tournament 2012 as a starter against South Korea, a game that ended 0–0. Fabián showed great skill and workmanship throughout the group stage match and helped Mexico reach the knockoff round. During the semi-final match against Japan, he proved vital by scoring in the 31st minute of the match to tie the game and later to win it 3–1, securing Mexico’s progression to the final against Brazil. During the final, he almost netted an over-head bicycle kick goal but it struck the post, though he did provide an assist for Oribe Peralta’s second goal of the match. Mexico would win the match 2–1 and thus win the Olympic goal medal. He played the entire tournament as Mexico’s second striker behind Peralta, and created a successful offensive deplete with him throughout the tournament. He finished the tournament with one goal from six matches, all as a starter. As a result, he became the top goal scorer for Mexico at the under-23 level, with 15 goals.

Marco made his first senior international cap against Venezuela in a 3–1 win on 25 January 2012.

On 12 December 2013, Fabián joined Cruz Azul on a two-year-long loan deal. Fabián made his Cruz Azul debut on 1 May 2014 against León, with the game ending in a 1–1 tie. On 15 February 2014, he scored a 92nd minute winning goal against Puebla. The goal was later nominated for the 2014 FIFA Puskás Award.

On 26 December 2014, after his loan deal expired, Cruz Azul opted not to exercise their purchase option due to Fabián’s high expense. He subsequently returned to Guadalajara and was assigned the number 33 shirt, since his preferred number 10 had since been taken; 33 was the same kit number he used when he made his professional debut in 2007. In his return to the Omnilife Stadium, on 18 January, Fabián scored his first goal of the Clausura 2015 tournament against UNAM in a 2–1 home victory. On 21 February 2015, Fabián then scored in a 1–2 away victory against Cruz Azul at the Azul Stadium. On 17 May 2015, he scored a hat-trick against Atlas during the 2015 Clausura quarter-finals, where Guadalajara won the match 4–1.

On 8 May 2014, Fabián was included in the final 23-man roster participating in the 2014 FIFA World Cup in Brazil. He debuted in a World Cup by coming on as a substitute in the first match against Cameroon in the 69th minute for Andrés Guardado. In Mexico’s second match, against Brazil, he came on in the 76th minute for Héctor Herrera. He also played in the third match against Croatia coming on as a substitute in the 84th minute, once again for Andrés Guardado.

On 18 December 2015, Guadalajara announced Fabián was sold to German Bundesliga side Eintracht Frankfurt for a transfer fee of US$4 million on a three-year contract. After completing his medical, Fabián was handed the number 10 jersey. He made his official debut coming on as a substitute for Haris Seferović in the 45th minute in a home match against VfL Wolfsburg on 24 January 2016. He created the play that led to Alexander Meier’s hat-trick that won the game 3–2.

He scored his first goal of the 2016–17 season—and his first Bundesliga goal—in a 2–1 win over Bayer Leverkusen on 17 September 2016. On 15 October, Fabián connected with his chest off a Timothy Chandler cross as Frankfurt held Bayern Munich to a 2–2 draw.

Fabián helped fund a football academy Guadalajara, Mexico. It provides football coaching, nutritional and psychological advice to participants under the direct supervision of Fabián himself. One graduate of the program reportedly signed with Brazilian club Santos FC in 2016. Fabián is also a fan of the baseball team Charros de Jalisco, and is a close friend to Javier Hernández.

In May 2018 he was named in Mexico’s preliminary 28-man squad for the 2018 FIFA World Cup in Russia, and in June 2018, he was named in Mexico’s 23-man squad for the World Cup. He would only appear in Mexico’s final group stage match against Sweden, substituted in at the 67th minute for Jesús Gallardo in a 3–0 loss.

On 8 February 2019 it was officially announced that Fabián had been transferred from Frankfurt to MLS team Philadelphia Union. Fabian signed a one-year deal with club options for the next two years. On March 2, Fabian made his MLS debut against Toronto FC, scoring his team’s lone goal of the encounter, losing 1–3. On October 20, in a playoff match against New York Red Bulls, he entered the match at the 103rd minute and scored the winning goal of the match, leaving the result 4–3 and giving Philadelphia their first playoff win in team history.

On 20 November 2019, Philadelphia announced they had declined the option on Fabián’s contract.

On 5 February 2020, he joined Qatar Stars League side Al-Sadd until the end of the season.