Velez overcame the Rosario club 1-0 in last season's Championship final in June and were even more emphatic winners this time round.
The hosts, who have made a mixed start to the new campaign, went ahead through a Lucas Pratto penalty after 34 minutes and never looked back.
Substitute Caseres doubled the lead after 71 minutes, running on to Pratto's through ball to finish smartly, and then made it 3-0 when he reacted first to tuck home after visiting goalkeeper Nahuel Guzman could only parry Pratto's shot.
Both sides finished with 10 men - Velez's Fabian Cubero following Newell's Pablo Perez for an early bath.
Newell's remain top despite losing their unbeaten record while Velez climb to sixth.