Poole, 19, moved to Old Trafford in 2015 from Newport County, where he played under current Cobblers boss Justin Edinburgh.
But his only United appearance to date was as a late substitute in the Europa League in February 2016.
The Wales Under-21 international comes in as competition for centre-backs Ash Taylor and Leon Barnett.
Edinburgh said: "He is a central defender who is comfortable on the ball. He is strong, he leaps well and he has all the attributes to be a top, top player.
"He is mobile and he will complement the other defenders we have at the club well."
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West Sussex Fire and Rescue said crews were called to a "ferocious fire" in the kitchen of the property in Harwood Road, Littlehampton, at 12:10 BST.
Police said a woman inside the house died, while two other adults were taken to hospital suffering from the effects of smoke inhalation.
The cause of the fire is currently being treated as unexplained.
Anyone who saw what happened at the time the fire broke out or who may have any other information is asked to contact Sussex Police.
League One side Northampton Town have signed young Manchester United defender Regan Poole on a season-long loan.
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A woman has died and two other people have been injured following a fire at a terraced house in West Sussex.