Aguero, City’s record scorer, has not featured in the champions’ last two games due to what was initially described as a minor muscle problem and he will again not be risked.
De Bruyne, who scored the winner against his former club at Stamford Bridge last season, has missed most of the campaign so far with knee problems.
When the Belgian suffered his latest setback early in November it was thought he could have an outside chance of returning to face the Londoners, but that has proved too optimistic.
Speaking at his pre-match press conference, manager Pep Guardiola said: “Both cannot play tomorrow. Both will be back soon.”
Chelsea have slipped to fourth in the table, 10 points behind leaders City, after losing two of their last three games but Guardiola sees it as a tough time to be playing them.
He said: “Always Stamford Bridge is difficult. I’ve travelled there many times as a manager and won once – last season. Most of the time I lose there.
“They are a good side, a really good team. You see the level of people on the bench – they don’t play regularly but they are excellent players. They are a real contender, an excellent team.
“How are they going to react after losing two games? I can imagine how intense, how aggressive and how committed they will be. That’s why it’s a good test for us, I will welcome that.”
Guardiola’s opposite number Maurizio Sarri has spoken of City in complimentary terms ahead of the game, describing them as “the best team in Europe, maybe the best in the world”.
Guardiola was too modest to agree. “Thank you but we are not the best,” he said. “To be the best we have to win the titles and we did not win the titles to be the best in the world.”
Guardiola feels Tuesday’s 2-1 victory at Watford, when City endured a nervy finish after dominating early on, underlines this point.
He added: “We could have dropped two points in the last 10 minutes. After 2-0 we were not the best side. There are many things we can do better and tomorrow we have a very demanding test for us.”
Guardiola has been impressed by the work of Sarri so far in his first season at Chelsea.
He said: “He needs time. Maybe they are not playing 90 minutes but when they play good for 50, 60, 70, 75 minutes they are excellent.”
Jan Vertonghen is back in the Tottenham squad for the trip to Leicester but fellow defenders Kieran Trippier and Juan Foyth are ruled out.
Vertonghen returns following a one-match ban but Trippier has a groin problem and Foyth a hamstring issue.
Mousa Dembele (ankle), Erik Lamela (thigh), Victor Wanyama (knee) and Davinson Sanchez (hamstring) are still sidelined.
Provisional squad: Lloris, Gazzaniga, Aurier, Rose, Vertonghen, Alderweireld, Walker-Peters, Moura, Dier, Son, Alli, Kane, Eriksen, Winks, Davies, Sissoko, Llorente, Vorm.
Jorginho and David Luiz are expected to return to Chelsea‘s starting line-up for Saturday’s visit of Premier League leaders Manchester City.
Blues boss Maurizio Sarri reported no serious injuries ahead of the clash and is expected to restore his first-choice line-up after Wednesday’s loss at Wolves, a second defeat in three league games.
Mateo Kovacic could start in midfield and Olivier Giroud could come in up front.
Provisional squad: Kepa, Caballero, Rudiger, Alonso, Fabregas, Jorginho, Kante, Barkley, Hazard, Pedro, Kovacic, Giroud, Zappacosta, Willian, Cahill, Christensen, Azpilicueta, Morata, Luiz, Emerson Palmieri, Loftus-Cheek, Hudson-Odoi, Ampadu, Bulka.