League leaders Doncaster took the lead near the end of the first half with a superb low strike from Tommy Rowe.
The O’s equalised just before the break through an unlikely source, as Tom Parkes slotted home to level the match up.
Former O’s striker John Marquis regained the advantage for the visitors with another clinical low strike, after an Orient mistake.
He grabbed his second late on to slot in from close range. Another former Orient player also got on the scoresheet Mathieu Baudry completed the rout shortly after with a great volley to secure all three points.
Danny Webb made five changes to his side they were defeated 5-0 away to Accrington Stanley on Tuesday, as Alex Cisak returns to the side between the sticks ahead of Charlie Grainger. Along with Liam Kelly, Aron Pollock, Nigel Atangana and Michael Clark who replaced the injured Nicky Hunt (Knee) and Callum Kennedy (Groin), with Freddy Moncur and Sam Dalby dropping to the bench repectivly.
Orient were the first to have a threat on goal, as Sandro Semedo’s corner was not totally cleared by Doncaster and Clark header from the clearance went just over the bar from inside the box.
Doncaster nearly took the lead 22 minutes in, when a looping cross into the box found John Marquis to head goalwards which was palmed away by Cisak at full stretch.
The visitors started to assert their pressure on Orient, as full-back Matty Blair whipped in the ball for Rowe to meet but was straight at Cisak.
Doncaster broke the deadlock nine minutes before the break, as Orient did not clear their lines properly and Rowe picked the ball up on the edge of the box and struck his shot low into the bottom corner beyond Cisak.
Orient equalised on the stroke of half-time, as Parkes carried on his run from his own box laid it off to Gavin Massey who fended off his man went passed another Doncaster defender and slotted in the unmarked Parkes who coolly tucked it passed Ian Lawlor – to go in at the break level.
In the second half, Doncaster almost regained the lead as the ball found its way into the six-yard box to Marquis who looked certain to hit the target but for a superb block by Parkes.
The away side did retake the lead, after a bad pass from Pollock straight into the path of Marquis whose shot went in off the post – out of the reach of Cisak.
Doncaster missed a great chance for their third, as Judd’s half clearance fell to Alfie May inside the box but he dragged his shot well wide of the target.
The away side spared another glorious chance, as they broke from an Orient corner and substitute Andy Williams was played in on goal but hit his shot well over.
Williams again was played through Orient’s own wrong doing and burst to the edge of the box but blazed his shot well over.
Doncaster grabbed their third with eight minutes to play, as Williams again broke free of the defence this time he squared the ball across goal for Marquis to fire past Cisak.
The away side got their fourth with four minutes remaining, as the cross came in and Baudry’s first time fierce volley flew into the bottom corner – to see off the O’s and take all three points.
Leyton Orient Lineup: 1 Alex Cisak, 4 Liam Kelly (C), 6 Tom Parkes, 7 Michael Collins, 11 Gavin Massey, 15 Nigel Atangana (88), 22 Sandro Semedo, 25 Aaron Pollock, 28 Josh Koroma (77), 29 Myles Judd, 34 Michael Clark,
Substitutes: 24 Sam Sargeant, 19 Teddy Mezague, 20 Rowan Liburd, 23 Freddy Moncur, 30 Sam Dalby (77), 31 Steven Alzate (88), 38 Dan Happe
Doncaster Lineup: 38 Ian Lawlor (45), 2 Craig Alcock, 5 Mathiey Baudry, 6 Andy Butler, 9 John Marquis, 10 Tommy Rowe, 17 Matty Blair, 24 Niall Mason, 25 Conor Grant, 26 James Coppinger (78), 39 Alfie May (72)
Substitutes: 13 Marko Marosi (45), 7 Gary McSheffrey (78), 11 Andy Williams (72), 12 Mitchell Lund, 14 Harry Middleton, 19 Liam Mandwville, 27 Cedric Evina
Attendance: 4,791 (816)