The centre was the Raiders' biggest weapon in their four-point win over Melbourne last round, pulling off a number of crucial plays late in the match while also opening the scoring with a try.
He finished the night with a team-high 182 run metres.
But after going down at training on Tuesday, Sasagi will join Josh Papalii on the sidelines for Thursday night's contest, with the veteran prop already ruled out for six to eight weeks with a calf injury.
Coach Ricky Stuart said it was a "massive" blow to lose Sasagi, attributing it to the heavy workload his players have faced of late.
"It's disappointing, we've had a very, very heavy load over the last 18 days - this is our fourth game in two-and-a-half weeks, basically - so something's going to give, and it did with Simi," Stuart said.
"I've had to lighten up the loads this week with all the travel we've had and then the short turnarounds and tried to look after them physically."
Stuart is mulling his replacement for Sasagi with his options including Savelio Tamale playing on the wing and Seb Kris shifting back to centre, or starting recruit Daine Laurie.
Included on the bench, Laurie is set to make his Canberra debut against the Tigers, where he played from 2021 to 2023 before two seasons with Penrith.
"It's very exciting for Daine," Stuart said of his first appearance for the club.
"He gives us great utility value - players in his positions have been doing quite well at the moment, so it's been very hard to get him in, but he's going to get his opportunity this week and it pays off for all his patience and hard work.
"The issue with Simi Sasagi now missing this game due to a slight hamstring strain, Daine gives me all different types of options."
Stuart expected the top-four Tigers, who suffered a one-point loss to Brisbane last round, to be a handful defensively.
"They're playing really good football at the moment and it'll be a tough contest," the Raiders coach added.
"Every game is testing your defence now with the style of the game, defensively it's a big job for edge defenders mainly.
"Big workloads for the middle, but coming off the back of quick play the balls makes it an even tougher gig for the boys on the edges."
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