López began in karting before entering the Formula Renault 2000 Eurocup in 2001, finishing seventeenth with one pole position and one fastest lap. He returned to the series in 2002 driving for Cram Competition, finishing fourth and scoring one victory. That same year he competed in Italian Formula Renault, where he won the championship with four victories, defeating Robert Kubica for the title. In 2003 he moved to the Formula Renault V6 Eurocup in partnership with the DAMS team and won the series outright with five race wins.
López stepped up to International Formula 3000 in 2004 with the CMS team, finishing sixth overall while also contesting selected Formula Renault V6 rounds. He raced in the inaugural GP2 Series season in 2005 with DAMS, finishing ninth, and switched to Super Nova Racing for 2006, ending the year tenth in the standings.
Returning to Argentina in 2007, López entered TC 2000 — the country's leading production-based touring car series — and finished fifth. He won the TC 2000 drivers' title in 2008 and defended it in 2009. He also joined Turismo Carretera in 2008 and Top Race V6 in 2009, winning the TRV6 championship that year. He was narrowly denied a remarkable treble in the 2009 Turismo Carretera, crashing out on an oil spillage on the eighteenth lap of the season finale when the title had been in reach. In 2012 he won the Super TC2000 championship for a third time with privateer outfit PSG16.
In 2007 he also raced in the American Le Mans Series and participated in the 12 Hours of Sebring with a Ferrari 430 GT, and competed in selected FIA GT Championship rounds in 2008 for the ACA Argentina team.
López was part of the Renault Driver Development programme from 2004 to 2006 and served as a test driver for Renault F1 in 2006. In November 2009 he confirmed a deal with the new US F1 Team for the 2010 Formula One season, subject to securing an eight-million-dollar sponsorship package. He was formally announced as a US F1 driver in January 2010, with former Argentine Formula One driver and politician Carlos Reutemann helping to assemble the funding. When US F1 collapsed before contesting a single race, López's Formula One opportunity evaporated. He returned to TC 2000 in 2010 driving for Honda.
López made his WTCC debut at the 2013 FIA WTCC Race of Argentina, substituting for a regular Wiechers-Sport driver. He won both the Yokohama Independents' Trophy races and took an outright race victory, immediately catching the attention of the championship's leading teams.
In 2014 he joined Citroën's factory effort and won ten races en route to the World Touring Car Championship title, clinching it at Suzuka. The Citroën C-Elysée WTCC proved dominant, taking seventeen victories from twenty-three races, and López surpassed both Yvan Muller and Sébastien Loeb — his own teammates — across the season. He retained the title in 2015 with another ten victories, then won again in 2016 with eight wins, completing an unprecedented three consecutive world titles for both driver and manufacturer.
In July 2016, López was confirmed as a driver for DS Virgin Racing in the third Formula E season, finishing ninth in the championship. He made a return appearance in the 2017–18 season, substituting for Neel Jani at Dragon Racing from the Marrakesh round onward.
López joined Toyota Gazoo Racing's FIA World Endurance Championship programme in February 2017, driving the No. 7 Toyota TS050 Hybrid alongside Kamui Kobayashi and Mike Conway. His debut at Silverstone ended early when he crashed the car around the halfway mark and was taken to hospital for precautionary evaluation of back pain, causing him to miss the Spa round. He was subsequently moved to the No. 9 car for the 24 Hours of Le Mans, where the car retired after being struck from behind by an LMP2 competitor. He returned to the No. 7 for Nürburgring, taking his first WEC podium with a third-place finish.
Following further seasons building experience in the hypercar era, López and his Toyota teammates won the FIA World Endurance Championship in 2020 and again in 2021. In 2021 he also co-drove the winning Toyota to victory at the 24 Hours of Le Mans, becoming the second Argentine driver to win the race after José Froilán González's triumph in 1954 — a gap of sixty-seven years.
López's career trajectory — from Argentine domestic championships through a failed Formula One attempt to the pinnacle of both touring car and endurance racing — represents one of the most varied and ultimately successful stories in modern motorsport. His three consecutive WTCC titles are among the most dominant runs in the championship's history, and his Le Mans victory gave Argentina a rare moment of recognition in the sport's most prestigious event.