Goals by Mikael Silvestre, a Chris Hargreaves own goal and Diego Forlan were enough to seal victory over a spirited Cobblers side, despite Lee Harper stopping a Forlan penalty early on.
Red Devils boss Sir Alex Ferguson decided to leave skipper Roy Keane and goalkeeper Tim Howard on the bench while Ruud van Nistelrooy, Ryan Giggs and Gary Neville did not travel for the match at The Sixfields Stadium.
In a pulsating opening few minutes, United were handed a relatively dubious penalty decision by referee Steve Bennett, as a cross from the left from Quinton Fortune saw Cristiano Ronaldo and Northampton's Chris Carruthers challenge for the ball in the air.
Bennett adjudged Carruthers to have pushed the Portuguese winger in the aerial challenge and pointed to the spot, much to the disbelief of the home faithful.
However, The Cobblers earned some measure of justice when Forlan's spot kick was brilliantly saved by Northampton goalkeeper Harper.
Seconds later, Ronaldo went close with a right-footed strike that crept by everyone at the far post and into touch.
Plenty of lively and open football was played by both sides in the first half and Northampton's Derek Asamoah caused United's backline some problems.
Asamoah forced the onrushing Roy Carroll into making a key intervention at the edge of the box that saw the ball run out for a goal kick.
The visitors, however, would not be denied an opening goal and despite a poor David Bellion strike at Harper on 29 minutes, United took a one-goal lead into the break.
John O'Shea's cross from the right found Ronaldo, who initially looked in an offside position, on the left of Northampton's box.
His right foot strike was stopped by Harper but in the ensuing melee in front of goal Silvestre bundled the loose ball over the goal-line.
The match to this point had been hotly contested, with Nicky Butt and Northampton's Hargreaves getting into a shoving match before order was restored.
Two minutes after the break, United increased their lead through the fortune of a Hargreaves own goal.
The visitors won a corner that was swung in and hit a number of bodies in front of goal before Hargreaves, who was trying to clear the danger, redirected the loose ball past the wrong-footed Harper for 2-0 - much to the disappointment of the home side.
Cobblers boss Colin Calderwood was also made to sweat over the fitness of Carruthers, who was stretchered off with a brace on his neck after a clash of heads making a challenge from the corner, and replaced by Luke Chambers.
Despite being 2-0 down, the home side kept pressing through Asamoah up front and they were unlucky not to score when substitute Marc Richards chested down a poor United clearance before hammering a strike against the bar.
But the visitors' superiority showed when a third goal was scored on 68 minutes when an O'Shea cross from the right found Ronaldo's head and his knockdown allowed Forlan to easily tap in past a sprawling Harper for 3-0.
With a 3-0 lead, Ferguson made changes and youngster Kieran Richardson nearly got on the scoresheet with a superb left-footed strike that Harper deflected on to the bar and away to safety before the Cobblers keeper made another good save from a deflected Forlan strike while Carroll made a fine save from a Cobblers free kick in the dying stages.
In the end, The Red Devils' professional approach was too much for the Third Division side and United go into Monday's draw for round five.
