The Millers went into the game looking to end some shaky form at their new home and Daniel Nardiello's penalty just before half-time gave the hosts the lead going into the break.
Aidy Boothroyd swapped one new signing for another as Roy O'Donovan came on for Emmauel Oyeleke but it was to no avail as goals from Ben Pringle and Michael O'Connor wrapped up the win for Rotherham, Clarke Carlisle's injury-time goal proving mere consolation.
A disappointing week then for Northampton having raised expectations of a promotion push with their recent good form. Boss Boothroyd will hope that the return to Sixfields, where his side have played well all season, will return them to wining ways.
He said afterwards: "The only complaint I have is with my players because that is the first time this season we have been outworked by an opposing team.
"They worked harder than us and that is something that doesn’t happen very often. If a team is on a poor run, though, then we usually end it."