The Uruguay international actually made his first Alaves start away to Real Betis, so the Andalucians will be familiar opposition for the winger in Thursday's Europa League round-of-16 second leg.
The Reds hold a 4-1 advantage from last week's contest at Old Trafford and are looking to advance into Friday's draw.
Harry Maguire is one of three other changes, coming into the team as captain, with Fred and Tyrell Malacia also introduced into the XI.
"First, they know the way of playing," Erik told MUTV about Pellistri and all of his younger players. "They know the rules, the principles of our game.