The France striker notched his team's third goal of a confident display in Transnistria, as Real Madrid exacted revenge for their shock 2-1 loss to Sheriff in Madrid earlier this season.
The victory sends the Spanish giants back to the top of Group D, two points clear of second-placed Inter Milan, who also qualified for the last 16 after beating Shakhtar Donetsk 2-0.
Madrid now only need to avoid defeat in their final group game against Inter at the Santiago Bernabeu to finish first in the group.
The defeat ends Sheriff's hopes of progressing, but a memorable debut Champions League campaign has already secured third place and a spot in the Europa League knockout phase.
Benzema, who was given a one-year suspended sentence for complicity in a bid to blackmail his former France team-mate Mathieu Valbuena on Wednesday, had an early effort ruled out for offside.