Márquez made his world championship début as a wildcard at the 2012 Spanish Grand Prix. In difficult weather conditions, Márquez scored points with a twelfth-place finish. He also made wildcard appearances at Estoril and Catalunya, scoring points on both occasions, with fifteenth and sixth respectively. After the mid-season break, Márquez moved into the series full-time from the Indianapolis Grand Prix onwards with Ambrogio Racing, replacing Simone Grotzkyj. He scored points in four of the remaining eight races, and ultimately finished the season in twentieth place in the riders' championship.

In 2013, the Estrella Galicia 0,0 team moved to KTM machinery, with Márquez joining Rins in the team full-time. After predominantly finishing fourth or fifth in the races during the first half of the season, Márquez achieved his first podium finish at the Indianapolis Grand Prix with a second-place finish behind Rins. Márquez recorded three consecutive third-place finishes at Silverstone, Misano and Motorland Aragón, before taking his first career victory at the Japanese Grand Prix. He finished the season in fourth position in the final championship standings.

For 2014, Márquez and Rins remained in the series and started as the championship favourites. However, in the opening third of the season, they were usurped by Ajo Motorsport rider Jack Miller, who won three of the opening five races. Márquez took successive wins in Catalunya and the Netherlands to reduce the deficit from 44 points to 7. Márquez started a run of five top-two finishes at the British Grand Prix, including another victory at Motegi, which saw him move into the championship lead ahead over Miller and open up a 25-point gap. Despite Miller winning two of the final three races, a third-place finish at the final round in Valencia saw Márquez clinch the title by two points. In the process, he and brother Marc Marquez became the first brothers to win world motorcycle racing titles.

For the 2015 season, Márquez moved up to the Moto2 World Championship with the Estrella Galicia 0,0 Marc VDS team and finished 14th in de standings. In 2016 Alex had a slightly better season and took his first Moto2 podium in the Aragon GP, ending the year in 13th. 2017 was a break through year for Alex Marquez as he won his first Moto2 race at the Spanish GP, ending a much more consistent season in 4th overall, followed up by another 4th place in 2018, despite not winning a race. Alex won the 2019 Moto2 world championship securing a double championship haul for the Marquez brothers. Alex Marquez was also the first rider to win a title in Moto3 and Moto2.

For the 2020 season, Alex will join his brother Marc at Repsol Honda Team replacing Jorge Lorenzo who retired at the end of the 2019 MotoGP season. Márquez was unexpectedly promoted from Moto2 to MotoGP when still contracted to Marc VDS for 2020 after the retirement announcement of Lorenzo in November 2019. Moto2 contracts can be broken if the rider is offered a place in MotoGP. Márquez' old seat in Moto2 for 2020 has been taken by Spaniard Augusto Fernández.