Flood, who has dropped to third in the England fly-half pecking order, proved he was back to his best with a 25-point haul as Leicester demolished their great rivals at a sell-out Franklin's Gardens, chalking up a fifth successive bonus-point win, a Premiership record.
Flood scored two of the Tigers' four tries in the win - he also kicked three conversions and three penalties - with the others coming from wingers Alesana Tuilagi and Horacio Agulla.
Northampton's tries came from England pair Lee Dickson and Chris Ashton, with Ryan Lamb kicking three penalties and Stephen Myler a conversion.
The ground was heaving and the tension even greater than usual for this midlands derby after a series of controversial matches between these two sides in recent times.
Northampton, who had won their previous two matches, made one change, with lock Samu Manoa replacing Mark Sorenson. But they were without four big guns, Dylan Hartley, Clark (both banned) Courtney Lawes and Wood.
Leicester, who started the day in third place after a fantastic run of eight wins in nine games, had to make a late change, full-back Scott Hamilton replacing captain Geordan Murphy. George Chuter took over as captain. Leicester also recalled England scrum-half Ben Youngs after a one-match ban.
Northampton led 6-0 after 13 minutes thanks to two penalties from fly-half Lamb.
It could easily have been more but Manu Tuilagi pulled off a brilliant try-saving tackle on opposite number George Pisi, who also got a bad bounce from a chip ahead after Hamilton failed to deal with the danger.
Leicester also had a lucky escape when Hamilton was again slow to deal with a bouncing ball in his own 22, but the game swung Leicester's way straight from the restart after Lamb's second penalty.
Lamb's attempted clearance was charged down by Leicester centre Anthony Allen and Flood pounced to score under the posts before adding the conversion.
Two minutes later Leicester led 14-6 after a brilliant piece of skill by Agulla, who chipped a defender, caught the ball and off-loaded inside to fellow winger Alesana Tuilagi, who went under the posts to make the conversion easy for Flood.
Leicester had another escape when flanker Julian Salvi just did enough to put off Ashton with the line at his mercy, while at the other lock George Skivington had a try chalked off for a forward pass by Allen.
Fierce Leicester pressure led to a penalty for Flood but that was cancelled out by Lamb's third penalty, which came after Agulla had come to Leicester's rescue with a great try-saving tackle on winger Paul Diggin after splendid work by Dickson and Ashton.
Leicester shot out of the blocks after half-time and fierce pressure led to their third try after just four minutes, Youngs putting Flood through a hole near the posts. Flood's conversion made it 24-9, and while he was short with a long-range penalty minutes later he made no mistake with one from 40 metres.
It was turning into the Flood show and he almost scored a third try but was beaten to his chip over the line by Foden.
In the 54th minute, Agulla scored Leicester's bonus-point try, beating Diggin in the right corner after more fierce pressure in the Saints line. Flood missed the conversion.
Northampton hit back six minutes later when Dickson scampered over after great work by his forwards and replacement fly-half Myler added the conversion.
Northampton should have scored again in the 63rd minute but Ashton fell over making a pass when he should have gone for the line.
Flood's third penalty in the 70th minute made it 35-16 before Tigers replacement prop Martin Castrogiovanni was sin-binned for a professional foul, and with two minutes left Ashton's hard work was rewarded with a try from Myler's chip.
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