López was born in the small town of Rafael Obligado, in Buenos Aires Province’s vast agricultural interior region. He arrived at Racing Club de Avellaneda at the age of 18 and, just two years later, made his Argentine Primera División debut in the 2003 Clausura; also in the side was a young Diego Milito leading the attack, and his subsequent exit to Genoa C.F.C. opened the doors to a regular first-team spot which López made his own in 2004.

López was crowned top scorer in the 2004 Apertura tournament, going on to score 26 goals in 71 league appearances and over 30 across all competitions. During his spell at the Estadio Presidente Juan Domingo Perón, he was nicknamed Licha.

In April 2005, López signed for FC Porto for a transfer fee of €2.3 million, at the same time of compatriot Lucho González. His agents, Global Soccer Agencies (later renamed Rio Football Services), retained 50% of the player’s rights– in the same transfer window, Luís Fabiano, whose rights were owned by GSA’s sister company, “Global Soccer Investments” (75%), left. He scored seven Primeira Liga goals in his first season in 26 games, repeating the feat the following campaign while appearing in one match less; he also found the net in the 1–1 home draw against Rangers in the 2005–06 UEFA Champions League, adding two to help defeat Hamburger SV (also in that competition but in the following edition, 4–1 home win).

In 2005, López was called up to the Argentina national team by José Pékerman, and he made his debut against Mexico on 10 March in a 1–1 friendly draw. After fantastic Porto performances, he was summoned three years later by Alfio Basile for exhibition games with Egypt, Mexico, the United States and Belarus.

In 2007–08, as Porto were crowned league champions for the third consecutive time, López was the competition’s top scorer, scoring 24 goals in 27 games and adding three in the season’s Champions League. On 20 April 2008, he netted twice – also being booked – in a 2–0 home win against S.L. Benfica; an offer from FC Zenit St. Petersburg was rejected midway through the campaign, and the Portuguese club eventually bought the remaining economic rights of the player for €4.4 million.

On 4 November 2009, López scored a late and decisive equaliser in a group game against Liverpool to ensure Lyon qualified for the knockout stage. Four days later he netted twice in three minutes in a 5–5 league draw to Olympique de Marseille, adding a further three the following month, against Lille OSC – the visitors led 3–1 at half-time, but were eventually defeated 3–4.

On 12 August 2009, López scored one goal in Argentina’s 3–2 victory over Russia at the Lokomotiv Stadium in Moscow. Nine days later, he was called by national team boss Diego Maradona for the decisive matches against Brazil and Paraguay for the 2010 FIFA World Cup qualification, but was overlooked for the final stages in South Africa.

On 30 March 2010, López scored twice in the 3–1 home victory against FC Girondins de Bordeaux in the Champions League quarter-finals (3–2 aggregate win), but missed the second leg due to suspension. He continued this good form with a goal in Lyon’s 2–1 away defeat of Stade Rennais FC, four days later.

On the final day of the season, López assisted Miralem Pjanić in a 2–0 home win against Le Mans, a result which placed Lyon second in the league table, with the subsequent direct Champions League qualification. On 9 May 2010, he was named Ligue 1 Footballer of the Year.

On 2 October 2010, López scored in a 3–2 away win over AS Nancy for Lyon’s second win of the campaign. He added two in the next ligue fixture – one from a penalty kick – a 3–1 defeat of Lille at the Stade de Gerland. On 20 October he found the net again, against Benfica in a 2–0 Champions League group stage win.

On 6 March 2011, after six scoreless appearances, López scored a hat-trick in the 5–0 thrashing of AC Arles-Avignon. In the 27th matchday he continued his run, opening the scoring in a 2–0 away win against FC Sochaux-Montbéliard. On 10 April, he netted in the 90th minute in a 3–0 home win over Lens and found the net in the following two home fixtures (both 3–2 wins), against Montpellier and Marseille, with his team eventually finishing in third position; on the final day of the season he scored a goal in the 2–0 win over AS Monaco FC, condemning the opposition to their first relegation in 35 years.

On 8 January 2012, López scored a hat-trick in a 3–1 win at AS Lyon Duchère for the Coupe de France. Three days later, he netted the 2–1 winner against Lille in the Coupe de la Ligue, in the 64th minute; on the 22nd, in his 100th competitive match for Lyon, he scored against Vendée Luçon Football for the French Cup round-of-32.

On 28 April 2012, López helped Lyon grab victory in the French Cup final, scoring the game’s only goal against US Quevilly. In late April of the following year, he announced he was leaving the club in the summer transfer window, with Garde commenting:

On 8 August 2013, López signed for Qatari club Al-Gharafa Sports Club, for a fee of €7.2 million. In late February 2015 he changed clubs and countries again, joining Brazil’s Sport Club Internacional on a two-year deal.

On 1 January 2016, two months shy of his 33rd birthday, López returned to Racing Club on a free transfer which had been agreed the previous month. In the 2018–19 season, he scored 17 league goals to lead the scoring charts and help his team win the national championship for the 18th time in their history.