The Reds have been knocked out of this competition by lower league sides in each of the last two seasons- to MK Dons and Middlesbrough respectively- but Mourinho has won seven of his eight cup ties against sides from outside the top flight, drawing the other.
Nobody in the visitors camp will be underestimating newly-promoted Northampton, however, with the hosts having enjoyed a solid start to life in the third tier.
They sit in eleventh place in the fledgling table after eight games and their 31-game unbeaten league run only ended on Saturday with a 3-1 reverse at Chesterfield.
Rob Page's side set up the tie against United with a 4-3 penalty shootout victory over West Bromwich Albion in the second round.
Northampton have never beaten the Reds with the most recent competitive outing ending in a 3-0 FA Cup win for United in 2004.
Mourinho made eight changes for the trip to Feyenoord last Thursday and then another five alterations for the visit to Watford at the weekend, so may be inclined to shuffle his pack again for a third away match in succession.
Michael Carrick looks set to feature for the first time this term, while younger members of the squad such as Timothy Fosu-Mensah, Axel Tuanzebe and Ro-Shaun Williams could also be involved.
Anthony Martial is a doubt after suffering a head injury in the first half at Vicarage Road and Phil Jones is out for a month with a knee injury while Luke Shaw and Henrikh Mkhitaryan are also doubtful with groin and thigh problems respectively.
Cup-tied winger Paul Anderson is the only definite absentee for the hosts having played for Bradford in an earlier round before joining the Cobblers.
"In these games against a team from another league it is important to always show them the respect as they are always the underdog with a lot to fight for so everyone is expecting the team to win but it is more difficult than that" said Mourinho.
"It is a game at an unfamiliar stadium against unfamiliar players and a team who came up last season so we don't know what to expect and it is a cup tie so there can always be a surprise.
"We have to take the game like any other and show Northampton the respect they deserve" added the United manager.
Form guide: Northampton D D W W W L United W W W L L L
Match odds: Northampton 10/1 Draw 21/5 United 1/3
Referee: Stuart Attwell
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