The Manchester City boss was speaking a day after Fifa president Gianni Infantino reported a plan to expand the World Cup finals to 48 teams from 2026 had been met with enthusiasm.
Guardiola is in favour of increasing the number of substitutes that can be used during games to give players more of an opportunity for a rest.
He said: “It’s not just English football, it’s all around the world. Now they talk about a World Cup of 48 teams — we are going to kill the players.
“Fifa will decide and we accept the decision and if we are not happy we go home.
“They are focusing on more and more and more — it affects the quality. I am thinking just for the players. They need to breathe, to (have a) break, to enjoy.
“This kind of thing is impossible because we are going to finish (the season), then after one week the World Cup then after three weeks we go to the pre-season, we go to China, the States, Australia.
“You play against Milan, Juventus, Madrid, and you have to win, people demand you have to play good. No preparation then you come back and it’s 11 months again and it’s the European cup.
“You do this for 10 or 12 years and we don’t think about the players. For that reason there has to be huge squads, more money for the clubs to spend.
“It’s just three substitutions now, why you cannot make four, five, or six? All the players are involved more than before, the coaches can use different tactics. Less injuries, more open games.
“Everything would be better. But OK, Fifa have another opinion.”
Guardiola has a depleted squad to face champions Leicester after Sergio Aguero, Fernandinho, and Nicolas Otamendi all picked up suspensions during last weekend’s 3-1 loss to Chelsea.
Yaya Toure’s drink-driving charge will not affect his chances of selection though. The 33-year-old was charged last Tuesday and is due to appear in court on December 13.
Guardiola said: “I spoke to him about the issue. He gave me his reasons. I trust him. I take the decisions on what I see on the pitch about his behaviour.”
Leicester boss Claudio Ranieri, meanwhile, insists the next two months will define the Foxes’ season.
The champions are just two points above the relegation zone only seven months after winning the Premier League.
Ranieri said: “This part of the season is our key moment. It’s important to fight together as a team.
“Our strength was this, if we made a dream last season it’s because we were together, not because we were a big team.” Jamie Vardy, Riyad Mahrez, Robert Huth, Andy King, and Islam Slimani will all return after being rested for the 5-0 Champions League humiliation in Porto.