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|Lyon are locked in a battle with Marseille for the third and final Champions League berth in France. (Photo: AFP/Philippe Desmazes)|
Dutch international Depay, who had a hand in all five goals against Metz last weekend, set up Mariano Diaz for the opening goal against Amiens on 30 minutes.
The former Manchester United player gathered a pass from Bertrand Traore and rolled the ball across to Mariano, who shifted back onto his right foot before finishing inside the near post for his 18th league goal of the season.
Depay nearly doubled the lead on the stroke of half-time when Amiens goalkeeper Regis Gurtner made a sharp save at his near post to keep out the forward's header.
Substitute Stiven Mendoza came closest to an equaliser for Amiens midway through the second half when his downward header was smothered on the line by Anthony Lopes.
Lyon captain Nabil Fekir returned after seven weeks out through injury for the final 15 minutes as the hosts eventually wrapped up the three points.
Gurtner and Prince-Desir Gouano combined to frustrate Traore and then Depay in a matter of seconds, but the latter gave Lyon room to breathe when he volleyed in a cross from the Burkina Faso striker on 83 minutes.
Traore himself got on the scoresheet two minutes later, following up after Fekir's effort was blocked to seal a victory that moved Lyon three points clear of fourth-placed Marseille.
"It's been a while since I played. The key thing is the victory and that my knee is fine, I don't feel any pain," said Fekir, whose last appearance came on Feb 25.
"There are a few matches left and we need to carry on like this until the end. The final sprint is underway, it will be difficult to catch up with Monaco (in second)."
Lille suffered a costly late collapse in a 2-2 draw at home to Guingamp, with an own goal from Junior Alonso and a 93rd-minute equaliser from Jimmy Briand keeping the 2011 champions in the bottom three.
Nicolas Pepe and Luiz Araujo had struck quick-fire goals just before the hour to leave Lille on the verge of a first win in 10 matches before Guingamp remarkably salvaged a point.
Mathieu Debuchy's renaissance at Saint-Etienne gained further momentum as the ex-Arsenal outcast hit an 82nd-minute winner at Strasbourg, while Nolan Roux scored twice for bottom side Metz in a 2-1 victory at Rennes.
South Korea international Kwon Chang-Hoon notched his ninth goal of the campaign for Dijon in a 1-1 draw at Claudio Ranieri's Nantes, who had led through a first-half effort by Prejuce Nakoulma.
Rudi Garcia's Marseille, who advanced to the semi-finals of the Europa League on Thursday with a thrilling 5-3 aggregate defeat of RB Leipzig, are back in domestic action away to Troyes on Sunday.
Paris Saint-Germain will reclaim the French title if they beat reigning champions Monaco at the Parc des Princes.
French Ligue 1 results on Saturday:
Lyon 3 Amiens 0
Lille 2 Guingamp 2
Nantes 1 Dijon 1
Rennes 1 Metz 2
Strasbourg 0 Saint-Etienne 1
Caen v Toulouse - postponed due to bad weather