The Exiles ran in two tries from Delon Armitage and David Paice as they claimed a 17-3 lead at the break.
Samoan flyer Sailosi Tagicakibau and Topsy Ojo added further tries in the second half and Mike Catt added a drop goal for the Irish.
Riki Flutey converted two tries and added a penalty, while Northampton only managed a Carlos Spencer penalty.
Northampton director of rugby Paul Grayson: "Jon Clarke dropping the ball at the end when a try was on summed it up.
"If that try had mattered I would have been worried about the decision but it didn't affect the outcome of the game.
"There was no lack of effort from the boys. They came off exhausted. We looked tired in the last 20 minutes."
London Irish: Horak; Armitage, Mordt, Catt, Tagicakibau; Flutey, Hodgson; Hatley, Paice, Rautembach; Casey, Kennedy; Roche, Dawson, Leguizamon.
Replacements: Collins, Flavin, Gustard, Murphy, Ojo, Willis, Pedro Tiesi.
Northampton: Kydd; Rudd, Clarke, Quinlan, Vilk; Spencer, Robinson; Smith, Richmond, Budgen; Damien Browne, Lord; Tupai, Harding, Daniel Browne.
Replacements: Hartley, Emms, Gerard, Fox, Noon, Howard, Pritchard.