The Argentine attacker only made his first start for the club following his summer move in midweek, when he scored as Spurs brushed Red Star Belgrade aside in the Champions League.
Lo Celso will now make his first Premier League start as Christian Eriksen drops to the bench from last weekend's lineup against Everton, while Harry Kane captains the side having now recovered from the illness which ruled him out at Goodison Park.
Sheffield United are the 29th different club Kane has faced in the Premier League, and he has scored against all of the previous 28 in the competition - the only such 100% record in the division's history.
Sheffield United, meanwhile, name an unchanged side from their 3-0 win over Burnley last time out as they look to build on a hugely encouraging start to the season.
David McGoldrick and Lys Mousset lead the line again, with the latter having been directly involved in five goals from his last three games, scoring twice and assisting all three in the win over Burnley.
TOTTENHAM STARTING XI: Gazzaniga, Aurier, Dier, Sanchez, Davies; Sissoko, Ndombele; Lo Celso, Dele, Son; Kane
Subs: Vorm, Alderweireld, Foyth, Winks, Sessegnon, Eriksen, Lucas
SHEFFIELD UNITED STARTING XI: Henderson; Basham, Egan, O'Connell; Baldock, Lundstram, Norwood, Fleck, Stevens; McGoldrick, Mousset
Subs: Moore, Sharp, McBurnie, Besic, Jagielka, Freeman, Robinson