Chile forward Sanchez, who joined United from Arsenal in a swap deal for Armenia's Henrikh Mkhitaryan on Monday, started wide on the left at a packed Huish Park.
The 29-year-old was frequently involved for United and his passes found Marcus Rashford and Ander Herrera for their goals either side of half-time, before he was substituted on 72 minutes.
The Somerset side had started brightly as Jordan Green's early effort was saved by Sergio Romero - who came in as one of 10 United changes - but the lowest-ranked side left in this season's FA Cup rarely looked likely to produce one of the competitions greatest ever shocks.
Jesse Lingard slotted in a third before Romelu Lukaku volleyed a fourth in stoppage time for the visitors, for whom victory came on manager Jose Mourinho's 55th birthday and in his 100th match in charge of the Premier League side.
The Portuguese - who signed a new contract to 2020 with the Old Trafford club on Thursday - has now won 62 of his first 100 games.
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Sanchez straight into the side
Sanchez was on the receiving end of several heavy tackles
Former Barcelona forward Sanchez, who scored 80 goals in all competitions for Arsenal in a three-and-a-half-year spell, became the first Chilean to play in a competitive first-team match for United.
Starting out wide, he gave the ball away repeatedly in the first half but was nevertheless lively and showed plenty of confident touches, cutting inside regularly.
He was on the receiving end of a very heavy tackle from Yeovil left-back Nathan Smith, before his curling effort from the resulting free-kick was held by Glovers keeper Artur Krysiak.
His simple pass found Rashford for United's opener, as the young England striker dribbled through the Yeovil box and lost the ball briefly before slotting home after the Glovers failed to clear their lines.
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After the break, Sanchez was involved again, sliding a ball to Herrera to slot home the second and mark his 150th appearance for the club in style.
For Yeovil, who knocked out League One Bradford City in the third round, the defeat came with the positive of £144,000 of television broadcast revenue, as they played in the fourth round for only the third time since 1949.
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Romelu Lukaku volleys home Man Utd's fourth goal
United, who haven't failed to reach at least the quarter-finals since 2014's surprise third-round loss to Swansea City under manager David Moyes, had won 2-0 at Huish Park in the third round just three years ago.
The FA Cup could prove to be United's best opportunity to win a trophy this season, having been knocked out of the Carabao Cup at Bristol City in December, especially with them trailing Premier League leaders Manchester City by 12 points.
Nevertheless, Mourinho was content to make sweeping changes to his starting side.
The visitors started relatively sluggishly, and stand-in keeper Romero was required to make an important early save to deny Yeovil's Green from close range.
But Mourinho's men controlled most of the remainder of the game and Yeovil - who remain yet to score against United after four meetings - will now return to focusing on their bid to avoid relegation to the National League.
Darren Way's spirited side sit just two points above the relegation zone, 21st in League Two.
For the Checkatrade Trophy quarter-finalists, defeat was their 10th consecutive loss in FA Cup meetings with top-flight sides, having now failed to scored in eight of those.
Man of the match - Alexis Sanchez
Sanchez lost the ball 31 times, but his risk-taking was rewarded as he set up a clutch of chances and two goals
Lingard's scoring streak continues - the stats
Manchester United have progressed from 13 of their last 14 ties in the FA Cup fourth round, with their only defeat in this run coming back in 2012 (1-2 v Liverpool).This was Jose Mourinho's 100th game in charge of Manchester United - he has won 62% of his games since taking over at the start of last season (P100 W62 D23 L15).The Red Devils have now won each of their last five games; their longest run of victories in all competitions since winning six in a row in September 2017.Marcus Rashford is the fourth different Manchester United player to score 10 or more goals in all competitions in 2017-18 (with Lukaku, Lingard and Anthony Martial) - Manchester City are the only Premier League team with as many.Zlatan Ibrahimovic (29) is the only Manchester United player who has scored more goals for the club under Jose Mourinho than Marcus Rashford (21).Alexis Sanchez has been directly involved in 15 goals in 15 appearances in the FA Cup (eight goals and seven assists).Jesse Lingard has scored 12 goals for the Red Devils in all competitions this term; one more than he did in the previous two seasons combined (11).This was the sixth time Jose Mourinho has taken charge of a game on his birthday, while he's won five of those six games, losing the other.Yeovil have lost each of their last 10 FA Cup games against top-flight sides, failing to score on eight of those occasions.
What's next
Yeovil face Grimsby on Tuesday while Manchester United return to Premier League action against Tottenham on Wednesday.
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