Having lost 2-1 in the reverse fixture in Lisbon, Lyon put itself in control when they moved into a 2-0 lead after 33 minutes of Wednesday's (AEDT) Group G encounter.
Depay's strike saw him become the first Lyon player since 2002 to score in four successive UEFA Champions League fixtures, with Joachim Andersen having headed the host into an early lead.
Substitute Haris Seferovic dragged Benfica back into contention with a VAR-awarded goal, but Lyon restored their two-goal cushion through Bertrand Traore, his superb effort in the final minute making sure Garcia's side moved within two points of group leaders RB Leipzig, who had won at Zenit earlier in the day.
Lyon went ahead within four minutes - Andersen meeting Leo Dubois' wonderful first-time cross and powering in the opener.
Benfica was dealt a further blow soon after, Ferro taken off on a stretcher after receiving lengthy treatment for a head injury sustained in a collision with team-mate Odisseas Vlachodimos.
Garcia's side had their second just after the half-hour, Depay tucking home on the volley after fantastic work from Houssem Aouar.
Benfica managed to stem the tide prior to the interval, however, and Anthony Lopes had to react swiftly to prevent Chiquinho hauling one back and then denying Seferovic after the interval.
With Depay subbed off at half-time due to injury, Jeff Reine-Adelaide almost curled in a sensational third for Lyon before Seferovic struck in the 76th minute, with the goal awarded after a check for offside.
However, Lyon substitute Traore having the final say, leaving Benfica planted to the bottom of Group G.