Olakau'atu was in agony after an attempted tackle on Viliame Kikau early in Sunday's second half, forced off the field in his first game since dislocating the same shoulder six weeks ago.
With Taniela Paseka still injured, Olakau'atu is unquestionably Manly's most important forward but is no certainty to play again this year as the ninth-placed Sea Eagles fight for a top-eight spot.
Tough clashes against the Sydney Roosters, Canberra and the Dolphins in the coming weeks will likely decide their season.
Manly can take comfort from having won all three games during Olakau'atu's first injury lay-off, but that resilience deserted them as Canterbury ran in five unanswered tries after the break.
Samuel Hughes' second try in the final five minutes left the match as the Sea Eagles' biggest-ever loss to Canterbury.
The second-half blitz moved the Bulldogs into second spot on the NRL ladder and helped them atone for the heartbreaking loss to Manly in last year's elimination final.
This year's Bulldogs are rightly aiming for a finals campaign more similar to the 1995 season, with the club commemorating the 30th anniversary of that year's premiership triumph on Sunday.
This was Canterbury's most dominant performance since Lachlan Galvin's mid-season arrival and the young halfback struck better chemistry with five-eighth Matt Burton than ever before.
After going into the break up by eight but still not comfortable, the Bulldogs scored the go-ahead try in the second half on the back of a Burton line break.
The five-eighth scurried inside on a 30-metre tear and right winger Jacob Kiraz scored his second four-pointer on the next tackle to confirm a three-score lead.
The Bulldogs went the length of the field in their next set and Bronson Xerri reached out under the posts to put his side on course for victory.
Late in the first half, Xerri had sprawled on the turf in pain after being struck in the face by Kikau's boots as his teammate flew to make a tackle.
Manly scored their lone try through Jason Saab on the Bulldogs' makeshift left edge shortly thereafter.
But Xerri returned in style after the break and had a second try late in the final 15 minutes, when the Bulldogs went into party mode.
Earlier, Canterbury had their first try following a regulation Burton bomb, spilt by 100-gamer Saab into the hands of a flying Hughes.
As Burton took the lead on kicking, Galvin flaunted his prized running game all day and triggered the shift that led to the Bulldogs' second four-pointer.
Galvin drew Ben Trbojevic in with a beautiful late ball, with a superb Connor Tracey (304 run metres) and Stephen Crichton also nailing their timing to put Kiraz over.
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