Zlatan Ibrahimovic stepped off the bench to fire United past battling Blackburn and into the FA Cup quarter finals.
Danny Graham had ended the Reds run of five consecutive clean sheets, only for Marcus Rashford to swiftly equalise after a stroke of magic from Henrikh Mkhitaryan.
With an unwanted replay looming, Jose introduced Zlatan and Paul Pogba, and the changes reaped dividends as the latter set up the former to send the Reds through to the last eight for a third successive season.
Rovers belied their lowly league status as Championship strugglers throughout and Owen Coyle's side pegged back their illustrious opponents with a fast start.
Sergio Romero saved well from Marvin Emnes but United did not heed that warning and Blackburn took a shock lead on 17 minutes.
Emnes was again involved as he superbly turned Marcos Rojo on the edge of the box and played in journeyman striker Graham who fired high beyond Romero - the first goal United had conceded in 450 minutes.
United responded strongly and went close soon afterwards as Ander Herrera was thwarted by a smart stop from Jason Steele.
It didn't take long to restore parity, however, thanks to Mkhitaryan's brilliance shortly before the half hour mark.
The Armenian magician glided beyond Danny Guthrie in midfield and played an exquisite, outside-of-the-foot through pass into Rashford, who ran through, rounded Steele and slotted in.
Craig Conway fired over from a tight angle and Jesse Lingard went close with a header
in an increasingly end-to-end fifth round tie.
Conway volleyed straight at Romero and Charlie Mulgrew lashed wide from distance, but United gradually exerted their authority on the match and Jose introduced Pogba and Ibra in search of the elusive winner.
It was the Swede who so nearly made an immediate impact, but Herrera's cross/shot narrowly evaded the outstretched leg of the onrushing striker.
Ibra didn't have to wait much longer for his chance to be our match winner yet again, though, as Jose's double change proved inspired.
Pogba collected the ball deep in midfield and picked out Zlatan with a inch-perfect through ball over the top.
Ibrahimovic did the rest as he chested down and fired home beyond the advancing Steele for his 24th goal of another stellar season.
Anthony Stokes had goal ruled out for offside and Romero saved from substitute Connor Mahoney as Blackburn pushed for a late leveller.
They were unable to force an Old Trafford replay, however, and United held out to secure a spot in the quarter finals in their bid for back-to-back FA Cup triumphs.
Overall team performance: 6.5/10
United Faithful Man of the Match: Henrikh Mkhitaryan