There was little to write home about in an uneventful opening 50 minutes but the game then hinged on two moments of individual quality in a 10-minute spell after half-time.
The first came from an unlikely source when a superb piece of improvisation from McDonald saw him turn, swivel and overhead kick the ball into the top corner before Holmes took the ball down brilliantly and let fly a fabulous long-range volley that rifled into the top corner.
From the moment of McDonald’s opener, the Cobblers had dominated and utterly outplayed Orient in a fantastic second half performance, and the win was crowned by two late goals from James Collins.
Collins scrambled home a corner to put Northampton 3-0 ahead before, in stoppage time, he finished off a slick counter-attack by sweeping a fierce low effort into the bottom corner.
In a season of highly impressive performance, this was undoubtedly Town’s best yet as Orient, who themselves are chasing promotion, had no answer to the movement, power and quality of the Cobblers, with the home side unable to properly test Adam Smith in the away goal.
The victory is also Northampton’s seventh straight league win and it keeps them firmly on course for promotion as they remain five points clear at the League Two summit.
Chris Wilder had been planning to name an unchanged starting XI for the third successive game but an injury suffered by Joel Byrom in the warm-up ruled him out of the game and meant Danny Rose came in for his Cobblers debut.
Orient named ex-Northampton defender Shaun Brisley and player-manager Kevin Nolan in their team, but after a sluggish start which saw neither goalkeeper test, it was the visitors who carved out the game’s first clear opening when, on 14 minutes, Ricky Holmes improvised brilliantly to produce a well-judged outside-of-the-boot cross for an unmarked James Collins but the on-loan striker volleyed wide when he should have hit the target.
That, however, remained the game’s only incident of note in a scrappy and dour first 30 minutes that saw possession being gifted away on a regular basis, Joby McAnuff’s tame shot saved by Adam Smith the only time either keeper was called into action.
Cobblers’ main threat came on the break and there was two particularly excellent opportunities to catch Orient short but first Marc Richards and then Holmes chose to go on their own instead of passing when they had options left and right.
That second miss came in a brief flurry of activity around the half-hour mark as Orient had their best sights of goal when Jay Simpson and then Nolan were both denied by some frantic last-ditch defending.
But the game then returned to being a scrappy affair and though Orient ended strongly, the first half ended goalless, a fair reflection of the game.
The opening stages of the second half suggested there would be little improvement but then came a stunning moment of quality that came very much out of character with the game.
On 53 minutes, a slip from Nicky Hunt was pounced upon by Martin whose cross seemed to have been dealt with but the ball then fell to McDonald.
With his back to goal and the ball going away from him, McDonald twisted his body and produced a fabulous piece of skill to scissor-kick the ball into the net, beyond the reach of a despairing Alex Cisak.
And that goal was the signal for Northampton to step up a gear and following a spell of pressure on the Orient goal, the visitors then doubled the lead with another goal of equal brilliance 10 minutes later.
This time, it was Holmes who produced it when he chested the ball down and unleashed a magnificent 25-yard volley that flew into the top corner.
The Cobblers had struggled to get going prior to McDonald’s opener but they had dominated since and deserved their two-goal lead as Orient struggled to muser a response.
Nolan came closest, just unable to reach Armand Gnanduillet’s low cross, before Simpson fired wide after swivelling inside the penalty area.
But instead of Orient finding a goal back, it was Northampton who went up another gear and added two late goals to put the seal on a superb away win.
First, a corner into the box fell kindly to Collins who controlled and then poked home from two yards out before, in stoppage time, the outstanding John-Joe O’Toole broke up an Orient attack, led the break out, found Lawson D’Ath who went on a fine bursting run before slipping through Collins, who clinically rifled into the bottom corner for his second of the afternoon.
That was the final action of note as Northampton coasted through three minutes of stoppage time to record a quite stunning away win that was fully deserved after a classy second half performance.
Orient: Cisak, Hunt, Baudry (c), Brisley, Shaw, Jahraldo-Martin (Gnanduillet 66), Payne (Palmer 40), Moore (Pritchard 78), McAnuff, Nolan, Simpson
Subs not used: Grainger, Essam, Clohessy, Atangana
Cobblers: Smith, Moloney, Diamond, McDonald, Buchanan, Holmes (Taylor 81), O’Toole, Rose, Martin (D’Ath 64), Collins, Richards (c) (Cresswell 87)
Subs not used: Clarke, Prosser, Adams, Hoskins
Referee: Paul Tierney
Cobblers fans: 1,135