The Sea Eagles captain went down clutching his left hamstring in the 13th minute of the Thursday night clash with the Cowboys in Townsville.
His history of similar injuries is long and the devastation on his face was palpable.
Former North Queensland star Brent Tate, on the sideline in commentary for Fox League, said it was "really disappointing to see".
Respected physiotherapist Brien Seeney, known on social media as "NRL Physio", said on X that it was Trbojevic's eighth hamstring injury in the past eight seasons, with four on each leg.
Manly's win was the third in a row for interim coach Kieran Foran, who continued his unbeaten run since taking over from sacked former head mentor Anthony Seibold.
Foran became the first coach to take over mid-season and win their opening three games since Brad Fittler when he took over at the Roosters in 2007.
Manly are now in fourth position and Foran gets his first match as coach at home against struggling Parramatta next week.
The Cowboys, who had won their previous four matches, made numerous errors and were a shadow of the side that had such a stellar previous month.
The Sea Eagles, great starters this season, opened the scoring through a try to winger Lehi Hopoate after slick work from five-eighth Luke Brooks.
Trbojevic exited the arena and Hopoate had his second in the 17th minute.
The Cowboys hit back through prop Coen Hess, but Manly half Jamal Fogarty then kicked for Ben Trbojevic to chase through and score.
Cowboys fullback Scott Drinkwater, in his 150th NRL match, spilled a kick. Hopoate swooped and could have scored himself but handed it off to hooker Brandon Wakeham for a 22-6 lead on the cusp of halftime.
Manly got some good injury news just before the break, with lock Jake Trbojevic passing a category-two HIA.
The Sea Eagles moved Tolutau Koula to fullback when Tom Trbojevic went off and brought Clayton Faulalo on at centre.
In the second half Koula, who did a great job in his new position, made a fantastic try-saving tackle on winger Brandon Burns, who for some reason was lethargic when he appeared certain to score.
Minutes later prop Taniela Paseka stormed over to seal the win.
Brooks was outstanding and was rewarded with a late try when he followed half Jamal Fogarty, who strolled through feeble Cowboys defence.
On-fire Manly prop Kobe Hetherington stood up in the absence of his skipper in a carve-up.
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