A scorcher from Darren Currie, two second-half penalties from Matthew Spring and a ninth of the season from Paul Furlong gave the Hatters a double over the Cobblers after their Johnstone's Paint Trophy win last month.
The visitors had been level at half-time through Bradley Johnson's missile-like strike, but it was the hosts who ran out worthy winners to move up to 14th in the table.
After their 4-3 embarrassment at Gillingham in the Johnstone's Paint Trophy last week, Luton saw Alan Goodall, Currie, David Bell and Drew Talbot return to the starting eleven.
Northampton made two alterations to the side that beat Port Vale 2-1 in their last outing, with Jason Crowe coming in for Ian Henderson who dropped to the bench and Andrew Holt replacing the suspended Poul Hubertz.
The Cobblers almost got off to a great start just 60 seconds in when Andy Holt was allowed a free header 12 yards out after Daniel Jones' corner but Currie hacked off the line.
Luton composed themselves and took the lead in spectacular fashion in the fourth minute when Don Hutchison's hopeful cross deflected off a defender into the path of Currie, who let rip with a curling right-footed effort that flew into the top corner of the net.
The hosts had a spring in their step, but they were almost caught flat-footed in the 13th minute when Jones' deep cross from the left bounced back off the top of the crossbar for Colin Larkin to then cross for Holt to put a ten-yard header wide.
Furlong was booked in the 22nd minute as Luton's frustrations grew and a minute later Northampton were level with a goal equally as impressive as Currie's earlier strike.
There didn't seem any immediate danger as Johnson picked up Larkin's lay-off 30-yards out, but the midfielder caught Dean Brill completely by surprise as he rifled a left-foot effort straight past him and into the net at the goalkeeper's near post.
The Hatters then had a lucky escape 11 minutes before the break as another Jones corner caught Luton napping as Crowe touched on for Mark Hughes to shoot from close range only to see the ball deflect wide off Brill's legs.
Luton were straight out of the blocks in the second period and went back ahead four minutes in when Currie's free-kick from the left caused confusion in the box and Talbot's close-range shot appeared to be blocked by Johnson with an arm.
Spring stepped up and made no mistake to continue his 100 per cent record from the spot with his fifth penalty of the campaign so far.
It was Luton who struck again in the 61st minute as Currie's curling free-kick from wide on the left-hand touchline was glanced in by the diving Furlong causing the ball to nestle into the corner of the net.
The Hatters continued to create and Currie was denied a second goal in the 78th minute when he linked up with Hutchison but saw his close-range effort blocked by Mark Bunn.
Spring rounded the game off with his second of the night, seventh of the season and sixth penalty of the campaign as he scored, fortuitously, in off Bunn in the final minute after Hughes had bundled over Furlong in the area.