Newcastle striker Isak was forced off in the 22nd minute due to injury away at Crystal Palace on Saturday after hitting the deck twice in the first half.
Fans would have expected to see his back-up Wilson replace him in the line-up - especially after Howe's comments about the player in his pre-match press conference.
Commenting on the 32-year-old, who made his return to action in the recent 2-0 defeat to West Ham, Howe said: "I can't speak highly enough of how he's faced the challenges in his career.
"It's a big moment for him now. He needs to stay fit, we need him to stay fit.
"We know what qualities he has on and off the pitch. He's a huge personality."
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But the ex-Bournemouth boss instead failed to chuck him on - presumably wanting to manage his game time - with Harvey Barnes coming on for Isak instead.
It lead to a shuffle up top, with winger Anthony Gordon moving into the middle so Barnes could feature on the right flank.
Howe's decision to leave Wilson on the bench left talkSPORT host Adrian Durham and reporter Olly Clink somewhat perplexed.
Durham remarked: "I'm a little bit puzzled by it because he's on the bench for a reason.
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"I know he's coming back. He came on Monday night and looked quite lively when he came on as well, although they lost the game.
"So I'm wondering how he's feeling about it because he'll be desperate to get on the pitch."
Clink then alluded to Howe's comments about Wilson ahead of the Magpies' trip to Selhurst Park.
He stated: "It's really interesting as well.
"He's been speaking in the week about how hard he has worked in order to come back from injuries."
Before adding: "I would say that I understand it given just how long he has been out and he is only just returning to the side."
Having the final say on the matter, Durham then said: "The match fitness won't quite be there for Wilson at the moment
"But it remains goalless and Newcastle's biggest goal threat has now gone off."
Newcastle fans will be desperate that Isak's injury is nothing serious ahead of next Wednesday's clash with Liverpool at St James Park.
No Newcastle player has scored more than the Sweden international's four Premier League goals this campaign.
Luckily for the Magpies, they did eventually take the lead with Anthony Gordon forcing a Marc Guehi own goal after a smart free-kick routine.