Spurs have not beaten their hosts at Old Trafford since 1989 and haven't secured a victory in the league against the Red Devils at all since 2001.
Former Tottenham attacker and ESPN analyst Waddle believes that a mental block is behind that statistic and that the key to reversing their fortunes is a different approach.
Asked if Spurs can run out winners against United, Waddle said: "Why not? Manchester United are stuttering at the minute. They're getting results but could have lost at Southampton, could have lost to Fulham and should have lost to Liverpool. I thought Liverpool were the better side and played excellently.
"They've also got a few injuries with Vidic and Valencia could be out as well.
"You look at Tottenham's squad and it is terrific. Dempsey and Dembele are terrific signings and if you look at that team, it's a really good lineup.
"I think it's more of a mental thing. They've got to go up there and say 'why can't we win at Old Trafford?' There is no reason why not.
"I've always said that teams like Man United, Chelsea and Man City can grind out results when they're not playing well. That is what Tottenham have lacked in the last few seasons."
The majority of bookmakers are offering odds of 5/1 for a Tottenham win.
Chris Waddle was speaking ahead of ESPN's live and exclusive coverage of Man United vs. Spurs at 4.30pm on Saturday. Visit espn.co.uk/tv for details.