After the sale of Karim Benzema to Real Madrid in the summer of 2009, López replaced him at Olympique Lyonnais, being transferred for a fee of €24 million, plus a €4 million bonus subject to performances.
On 8 August, he scored on his Ligue 1 debut from a last-minute free-kick at Le Mans FC, in a 2–2 draw.
He added a hat-trick against R.S.C. Anderlecht in the second leg of the Champions League qualifying round, in an eventual 8–2 aggregate win.

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 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.

After a one-month spell without a goal, López finally added to his account by grabbing a last-minute goal in a 3–1 away win against RC Lens.
He added two in another away fixture, against Montpellier HSC (2–1, the second coming in the fifth minute of stoppage time).
Three days later Lyon, needing a point to secure passage to the knockout stages of the Champions League, played host to Hapoel Tel Aviv FC, and he opened the scoring in the 62nd minute of an eventual 2–2 home draw.

López scored again in the next match for L'OL in a 2–0 win over Toulouse FC, putting them up to second place in the table.
He also found the net in the following game, a 1–1 draw against title holders Marseille at the Stade Vélodrome.

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.

López started 2011–12 in fine form, scoring in the first two games, his first coming in the early stages of a 3–1 win at OGC Nice.
The following weekend, against newly promoted AC Ajaccio, he hit the post twice in the first ten minutes and had several shots saved by Guillermo Ochoa, but was able to salvage a point for new coach Rémi Garde on his home debut with an excellent header in the 83rd minute.

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:
I also wanted to make a huge tribute to Licha (López).
I will not forget wh
After the sale of Karim Benzema to Real Madrid in the summer of 2009, López replaced him at Olympique Lyonnais, being transferred for a fee of €24 million, plus a €4 million bonus subject to performances. On 8 August, he scored on his Ligue 1 debut from a last-minute free-kick at Le Mans FC, in a 2–2 draw. He added a hat-trick against R.S.C. Anderlecht in the second leg of the Champions League qualifying round, in an eventual 8–2 aggregate win.
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 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.
After a one-month spell without a goal, López finally added to his account by grabbing a last-minute goal in a 3–1 away win against RC Lens. He added two in another away fixture, against Montpellier HSC (2–1, the second coming in the fifth minute of stoppage time). Three days later Lyon, needing a point to secure passage to the knockout stages of the Champions League, played host to Hapoel Tel Aviv FC, and he opened the scoring in the 62nd minute of an eventual 2–2 home draw.
López scored again in the next match for L'OL in a 2–0 win over Toulouse FC, putting them up to second place in the table. He also found the net in the following game, a 1–1 draw against title holders Marseille at the Stade Vélodrome.
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.
López started 2011–12 in fine form, scoring in the first two games, his first coming in the early stages of a 3–1 win at OGC Nice. The following weekend, against newly promoted AC Ajaccio, he hit the post twice in the first ten minutes and had several shots saved by Guillermo Ochoa, but was able to salvage a point for new coach Rémi Garde on his home debut with an excellent header in the 83rd minute.
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:
I also wanted to make a huge tribute to Licha (López). I will not forget wh
Lisandro López