The Swiss attacker was brought on 20 minutes from time and made a huge impact on the game, putting his side back in front 144 seconds after being introduced and sealing the Reds' 14th league win of the season with a second late on.
United, previously unbeaten in their previous eight meetings with arch-rivals Liverpool in all competitions, managed just two shots on target all afternoon - one of those being Jesse Lingard's close-range finish from an Alisson Becker howler to cancel out Sadio Mane's opener.
Liverpool dominated the second half and were rewarded through substitute Shaqiri, who becomes the first Reds player to score multiple goals in a home Premier League game in this fixture since Dirk Kuyt in March 2011.
Not since 1990 had Liverpool enjoyed a bigger points margin on United heading into a league game, and the gulf between the sides was there to see in the opening quarter of the match.
After playing out back-to-back goalless draws here, it soon became clear that there would be goals on Merseyside as Roberto Firmino and Mohamed Salah both had efforts kept out in a high-tempo opening 12 minutes.
Liverpool's attacking play was rewarded a quarter of the way through as Mane ended his eight-game scoring drought by getting in front of Ashley Young, chesting down Fabinho's lofted pass and tucking the ball under David de Gea without the ball touching the ground.
Dejan Lovren was then guilty of missing a good opportunity from close range once Firmino worked the ball back into the centre-back's path, and that would prove costly six minutes later when Lingard snatched an equaliser.
United had a Young goal correctly ruled out for offside against Romelu Lukaku early in the match, while Marcus Rashford got in a well-struck shot from range, but there was nothing to suggest that Liverpool's goal was under threat.
The equaliser was gifted to them by Alisson, though, with the Brazilian failing to keep hold of Lukaku's low cross, spilling the ball into the path of Lingard to score his first away league goal since New Year's Day.
Mane had a shot kept out from 20 yards after once again being teed up by Fabinho as Liverpool attempted to regain their advantage, but the tempo of the match dropped as the teams went into the break all square.
With his side badly overrun in midfield during the first half, Jose Mourinho - boasting the best away record of any boss to have managed five or more games at Anfield before today - brought on Marouane Fellaini for Diogo Dalot and reverted to a four-man defence.
The change provided United with some much-needed midfield steel, but it was still Liverpool who were on top throughout the second half as Firmino's poked shot - after showing some sublime footwork to get away from a few players - was blocked by De Gea.
The substitution paid instant dividends as Shaqiri rifled the ball in off the underside of the crossbar minutes after being introduced, profiting from some good work from Mane out wide in the build-up.
De Gea flicked Mane's cross as far as Shaqiri, who had enough time to pick his spot - with a helping hand from a touch off Young - despite United having six players inside the box.
A second Shaqiri goal followed before full time, sending his latest shot flying past De Gea, this time with a telling deflection off Eric Bailly - brought into United's starting lineup shortly before kickoff due to a Chris Smalling injury.
Defeat for United leaves them sixth in the table and now 11 points adrift of fourth-placed Chelsea.
LIVERPOOL (4-3-3): De Gea; Darmian, Smalling, Lindelof; Dalot (Fellaini 46'), Lingard (Mata 85'), Matic, Herrera (Martial 79'), Young; Rashford, Lukaku
MANCHESTER UNITED (3-5-2): Alisson; Clyne, Lovren, Van Dijk, Robertson; Fabinho, Wijnaldum, Keita (Shaqiri 70'); Mane (Henderson 84'), Firmino, Salah body check tags ::