Key striker Callum Wilson will also miss out through a hamstring injury, having netted 12 goals in the Premier League this season, playing a major role in the Magpies' survival.
In Wilson's absence last time out, midfielder Joe Willock found the net for the fifth consecutive match, and the Arsenal loanee should again feature from the outset on Wednesday.
Meanwhile, forward Joelinton netted his fourth goal of the season from the penalty spot in that match, giving the Brazilian renewed confidence coming into the final two matches of the season.
Aside from Lascelles's injury, Newcastle's defensive options have been further hit by the suspension of centre-back Fabian Schar, and the Swiss international will serve the final game of his three-match suspension on Wednesday after a red card in their 2-0 defeat to Arsenal at the beginning of May.
With the limited options, the Tyneside outfit were forced to line up with a makeshift back three of Emil Krafth, Federico Fernandez and Paul Dummett for the Manchester City clash, while Ciaran Clark will also be pushing for a starting spot after a spell on the bench.
Newcastle United possible starting XI: Dubravka; Krafth, Fernandez, Dummett; Murphy, Willock, Shelvey, Almiron, Ritchie; Joelinton, Saint-Maximin
Watch the Sports Mole Football Shorts prediction for this game below: