Watkins slid home the only goal of the game on 26 minutes, and though Orient had a couple of opportunities they were unable to find a leveller.
Orient made two changes to the side which lost out 2-1 to Blackpool at the Matchroom Stadium on Saturday with second-year scholar Myles Judd coming in for his full debut at right back for the injured Yvan Erichot, while weekend goalscorer Paul McCallum replaced Ollie Palmer up front.
The first shot in anger fell to the O’s and skipper Robbie Weir in the fifth minute but after taking one touch shot he over from just outside the area.
Up the other end Reuben Reid tried to work an opening but a combination of Weir and Kennedy averted any potential danger for Alberto Cavasin’s side.
O’s were enjoying much more of the possession but were struggling to turn that into opportunities, though did force a few corners which came to nothing.
Gavin Massey gave away possession midway through the half and that set the Grecians on to a counter attack with Reid. After a mazy run he laid the ball into the path of David Wheeler but he was met by a fine sliding challenge from Tom Parkes to snuff out the potential threat.
Parity was shortlived though as with their next attack Exeter broke the deadlock. Wheeler pulled the ball back for Ollie Watkins and he slid the ball home past Alex Cisak.
Orient had an instant chance to reply when Simpson intercepted a weak back pass from the Grecians, but the onrushing Exeter goalkeeper Christy Pym did enough to prevent the striker getting a shot away.
Simpson then lashed an effort over after some neat build up play from the forward and Massey as the O’s looked for a leveller, before Nicky Hunt, fresh from his goal against Colchester United, fired a free-kick over the bar.
The visitors could have doubled their lead with just five minutes of the half remaining when a fine deep-ball in from Craig Woodman found the head of Reid who nodded agonisingly wide.
Orient ramped up the pressure in the latter stages of the first period though with Michael Collins and Atangana looking to get the O’s ticking. A rampaging run from the latter almost presented an opportunity for Collins, but the Grecians put it behind for a corner.
Collins again went close soon after and his ball across the six-yard box was hacked agonisingly wide by Exeter skipper Jordan Moore-Taylor and proved to be the final action of the half.
Both Robbie Weir and Callum Kennedy were replaced at the break by O’s boss Cavasin, with Sandro Semedo and Alan Dunne on in their place respectively.
It was only the feet of Cisak who kept a Liam McAlinden effort out following a pull back from the by-line in the early stages of the second period.
Chances were few and far between in the opening exchanges with the closest either side coming to a goal being a chance for former O’s loanee Jake Taylor, but the effort was held comfortably by Cisak.
But twice in a matter of seconds the O’s went agonisingly close to levelling matters. Atangana met a cross from the right which forced Pym into a solid save before Simpson saw a close-range deflected over from the rebound.
Time was ticking away for Orient to net a leveller and Reid showed Parkes a clean pair of heels as he drifted into the box off the left, but his cross was blocked behind for a corner by Hunt.
A minimum of four minutes added on time was signalled but despite the O's having possession, they were unable to find a late goal to rescue a point.
Orient: Cisak, Kennedy (Dunne HT), Parkes, Hunt, Judd, Massey, Weir (c) (Semedo HT), Atangana, Collins, McCallum (Palmer 59), Simpson.
Subs: Sargeant, Pollock, Dalby, Ochieng.
Booked: Massey (39), Atangana (42), McCallum (59), Collins (65), Hunt (71)
Exeter: Pym, Woodman, Croll, Moore-Taylor (c) Sweeney, James, Taylor, McAlinden (Oakley 66), Wheeler (Stacey 66), Watkins (Simpson 88), Reid.
Subs: Olejnik, Grant, Jay, Brown.
Goals: Watkins (26)
Booked: Wheeler (13), Watkins (85)
Attendance: 2,926 (316 Exeter City fans)
Referee: Tim Robinson