A clinical Danny Johnson hat-trick sent Town to defeat at The Breyer Group Stadium.The Leyton Orient frontman's two clinical finishes in the first half proved too much to come back from, with the O's top scorer heading home from a corner to wrap up the points for his side.
With Simon Weaver still absent as a result of a positive Covid-19 test, Paul Thirlwell brought Aaron Martin and Dan Jones into the starting line-up, two players who had made a positive impact when coming off the bench on Saturday.
The hosts meanwhile made three changes to their line-up, most notably a return to the side for to scorer Danny Johnson.
It was Town who created the first opening of the afternoon, Josh Falkingham starting his 150th Town appearance with an incisive pass to Ryan Fallowfield, though the marauding full back's cross was well dealt with by Lawrence Vigouroux in the Orient goal.
Despite Town making most of the early headway, the hosts struck on the counter attack with 18 minutes on the clock, Johnson latching onto Conor Wilkinson's pass and firing low past James Belshaw.
Town were caught on the counter again on the half hour mark, but had Belshaw to thank as Town's stopper kept out Wilkinson's effort with Orient in a 5 vs 3 situation.
The red-hot Johnson struck again in the 31st minute, judging the flight of the ball over Jake Lawlor to perfection and sending a volley across goal and in.
Those two finishes proved to be the difference in a first half where Town enjoyed plenty of possession in the opposition half, but couldn't create a meaningful opening and headed back to the changing rooms two behind.
Thirlwell opted to introduce Warren Burrell at half time and the change looked to have worked as Town started brightly, though when George Thomson did put the ball in the back of the net it was ruled out for a foul on the goalkeeper.
Orient weren't given much away though and added a third to put the game to bed in the 73rd minute, Johnson completing his hat-trick when heading home from a corner.
The defeat leaves Town in 14th place, four points away from the Play-Off places with a trip to Mansfield to come on Tuesday.
Harrogate Town: Belshaw, Fallowfield, Jones, Falkingham, Thomson, Martin (Stead 60), Lawlor (Burrell 45), Kiernan (Walker 84), Kerry (Kirby 60), Muldoon, Hall
Subs not used: Cracknell, Lokko
Booked: Burrell, Jones
Leyton Orient: Vigouroux, Ling, Widdowson, Cisse, Happe, Coulson, McAnuff (Dayton 78), Wilkinson (Dennis 82), Brophy (Maguire-Drew 82), Kyprianou (Wright 87), Johnson
Subs not used: Sargeant, Thomas, Akinola
Goals: Johnson 18, 31, 73
Booked: Coulson, Widdowson
Referee: N Hair