In the line-up for the first time since Boxing Day as Jose Mourinho made three changes with Paul Pogba ruled out through injury, Rashford scored a first-half brace to boost United's hopes of finishing second to runaway leaders Manchester City.
The England international ended a run of 10 Premier League matches without a goal to send United five points clear of third-placed Liverpool in the 200th competitive meeting between the sides, though Tottenham could close to within four by beating Bournemouth on Sunday.
Jurgen Klopp made five alterations to the side that secured progression to the Champions League quarter-finals against Porto on Tuesday, with Virgil van Dijk, Andy Robertson and Trent Alexander-Arnold reinforcing the defence, while Alex Oxlade-Chamberlain and Mohamed Salah returned further up the pitch.
But that backline was bullied by Romelu Lukaku, who proved a magnet for the long balls from which he helped create Rashford's goals - the first of which came after a delightful change of direction in the 14th minute.
An own goal from Eric Bailly on his first start since November having been sidelined with a knee injury gave Liverpool hope during an improved second-half display, but the Red Devils held on for a potentially crucial victory.
Klopp on Friday said the clash was not "an attacking team against a defending team" but that was exactly how the opening stages played out, with United sitting back and Liverpool controlling possession.
It was the hosts who took the lead, though. David de Gea's goal-kick was flicked on to Rashford by Lukaku, and he brilliantly chopped inside of Alexander-Arnold and fired inside the far post.
Gooallll @ManUtd— Usain St. Leo Bolt (@usainbolt) March 10, 2018
Van Dijk wasted a glorious chance to equalise in the 23rd minute, his shoulder rather than head connecting with a corner from James Milner - wearing the captain's armband as Jordan Henderson sat out with a dead leg - as he missed the target from inside the six-yard box.
United made the most of that reprieve by doubling their advantage just 62 seconds later, again from a long pass from deep.
Van Dijk's challenge on Juan Mata after brilliant work from Lukaku inadvertently sent the ball to Rashford, who guided it beyond an out-of-position Loris Karius with the help of a nick off Alexander-Arnold.
It should have been three when Alexis Sanchez picked out the unmarked Mata in the middle of the area before half-time, but the Spain international sent his overhead kick wide.
Liverpool stepped up a gear after the restart and saw penalty claims for Ashley Young's foul on Salah and a handball by Antonio Valencia turned down by referee Craig Pawson.
They were rewarded in the 66th minute when Sadio Mane beat Scott McTominay for pace down the left and sent in a cross that Bailly approached with the wrong foot and sent into the back of his own net.
There were boos when Mourinho replaced Rashford with Marouane Fellaini to add an extra body in midfield with 20 minutes remaining, and the Belgium international was fortunate not to concede a penalty when he sent Mane to ground.
Klopp sent on Georginio Wijnaldum and Dominic Solanke as Liverpool fought to restore parity, but Salah sliced a wild volley over in the sixth minute of stoppage time as United held on for a third successive league win.
Key Opta Stats:
- Manchester United defeated Liverpool for the 68th time in league competition; this is the most defeats that Liverpool have suffered against a single side.
- United have won four of their eight games against fellow 'big six' sides in the Premier League this season (W4 D1 L3), twice as many as they managed in the whole of last season (W2 D4 L4).
- Liverpool have won only one of their seven Premier League games on the weekends immediately following playing a Champions League game this season (W1 D4 L2).
- United have won 20 of their 30 Premier League games this season, already surpassing their totals in both 2016-17 (18) and 2015-16 (19) and equalling their number of league wins in 2014-15 (20).
- Only United (67) have profited from more own goals in the Premier League than Liverpool (58).
- Manchester United had just two shots on target in this match – both of which were scored by Marcus Rashford.
- He has scored seven of his 16 Premier League goals against teams in the 'big six' (44%).
- Romelu Lukaku now has seven Premier League assists this season; more than he has in any previous campaign.