Goals from Rodrigo Betancur, Giorgian de Arrascaeta, Edinson Cavani and a Luis Suarez penalty saw Uruguay romp to a second successive victory under new coach Diego Alonso that propelled them, temporarily at least, into the final automatic qualification berth in the single South American group.
But it was Manchester United youngster Pellistri, who has spent the last year on loan at Spaniards Alaves, who shone brightest.
His mazy run set up the second goal and his trickery won the penalty converted by Suarez.
With two qualifiers left at home to Peru and away to Chile, Uruguay's World Cup destiny remains in their own hands.
They had a dream start in Montevideo as Cavani's first minute cross was half cleared to the edge of the box where Betancur hit a sweet half volley that clipped a heel and skidded past Wuliker Farinez in the Venezuela goal.
Uruguay were dominant and doubled their lead on 23 minutes after Pellistri showed great trickery to beat three players on the right and cut the ball back for De Arrascaeta to slot home from close range.
Cavani, who had a second half goal ruled out for offside, all but sealed the victory in first half stoppage time with an opportunistic overhead kick from six yards out as Uruguay's players were lining up to finish off their weary opponents.
Pellistri continued to torment Venezuela down the right in the second half and won a penalty off Nahuel Ferraresi.
Farinez saved Suarez's spot kick but referee Bruno Arleu ordered it be retaken due to encroachment and the Atletico Madrid striker made no mistake the second time.
Josef Martinez netted a consolation on 65 minutes after a defensive mistake from Jose Gimenez.