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.
Madrid were dominant but struggled to find a way through, with Rodrygo shooting tamely at home goalkeeper Giorgos Athanasiadis in the 18th minute.
But the away side did forge ahead on the half-hour mark through David Alaba.
The Austrian defender's free-kick was deflected by the Sheriff wall and past the helpless Athanasiadis.
The hosts were struggling to get out of their own half and Dani Carvajal almost added a second for Madrid when he volleyed narrowly over the crossbar.
The 13-time European champions did double their advantage in first-half stoppage time, though, as a fantastic move was ended by Toni Kroos' first-time shot which flew in off the crossbar and was awarded by goalline technology.
Benzema got his goal in the 55th minute, finding space on the edge of the box and drilling the ball into the bottom corner to score for the 15th time this season.
It was also the 76th goal of the striker's Champions League career.
Sheriff had scored in each of their first four group games and had a flurry of chances midway through the second half, with Real goalkeeper Thibaut Courtois making two saves and a cross hitting the post.
But it was ultimately a comfortable outing for Madrid as they made the knockouts for a 25th consecutive year.
Standout matches today