United's extensive cup adventures for the 2014-15 campaign are over after conceding three goals in a ten minute spell on Tuesday evening.
Preston North End go through to the fifth round tie with Manchester United after coming from behind to win at Bramall Lane.
Jamie Murphy gave the Blades a half-time lead but two goals from Paul Gallagher and one from Paul Huntington gave Preston their first victory over Nigel Clough in the fourth meeting between the teams this season.
For the second game in succession, boss Clough made ten changes. He reverted to the starting XI that faced Spurs at Bramall Lane with only Basham retaining his place from the win over Swindon. Five of Saturday's team were ineligible, as were new boys Holt and Done.
Murphy had a couple of early runs at Wiseman but the initial chances went the way of the visitors. A Laird effort was at Howard, whilst Basham's short back header presented Davies with a chance but his half-volley struck in the inside of a post and stayed out. Howard was also forced to save a long-range effort from Gallagher on 15 minutes.
Deflected efforts at both ends caused the goalkeepers concern before trickling wide, McNulty for United and Humphrey for the visitors and Howard was called upon twice in the space of three minutes - firstly pushing away a Clarke header from Gallagher's corner and then United's number one was at full stretch to divert Laird's header.
United weathered the onslaught and then took the lead on 38 minutes. Doyle robbed Humphrey before delivering a low pass that allowed MURPHY to cut inside Wiseman and find the net with a shot which Stuckmann should have done more to keep out.
The final chance of the first half also fell to the Blades. In injury-time, Baxter got the better of both Gallagher and Brownhill but his 20-yard shot was push away by Stuckmann, low down to his left.
The second half kicked off with a booking for each team, McNulty for United after an accumulation of fouls. Predictably, Preston attempted to push United back and on the hour Laird's effort was pushed away by Howard, who was quickly on his feet and linking with Harris to prevent Humphrey latching on to the rebound.
However, the visitors were soon level. A Harris foul on Humphrey was just on the edge of the box but GALLAGHER curled into the top corner with pace from 19 yards.
United replaced Scougall with Reed but Preston netted again with their next set piece. Laird's inswinger received the slightest of touches from HUNTINGTON but it was enough to find the net.
The second half got worse for the Blades as Preston added a third. This time McEveley was adjudged to have fouled Humphrey in the box and GALLAGHER's penalty was drilled past Howard's right arm.
Basham's header from Baxter's corner was wide as United looked to respond but Gallagher went close twice more for the visitors. De Girolamo replaced Doyle in an attacking move but the Blades could not threaten the visiting goal in the later stages.
Even in the four minutes of added time all the Blades could muster was a long-range effort from McEveley, which flew into the Kop, and a sliding shot from Murphy, which Stuckmann blocked with his legs.
Blades: Howard, Harris, Basham, Flynn, Doyle (De Girolamo 79), Murphy, Scougall (Reed 63), Baxter, McNulty, McEveley, Campbell-Ryce.
Unused: Alcock, Davies, Turner, Kennedy, Cuvelier.
Preston: Stuckmann, Laird (Welsh 88), Wiseman, Clarke, Humphrey (Reid 83), Kilkenny, Davies (Garner 88), Gallagher, Woods, Huntington, Brownhill.
Unused: Wright, Browne, Hudson, Ebanks-Blake.