Last season, Palace ended City's record 18-game winning run last season but Guardiola's team still amassed 100 points as they cruised to the title.
In a much tighter title race this season, with City just behind Liverpool, the Eagles' 3-2 win at the Etihad in December could yet be the game that costs Guardiola's men.
A visit to Selhurst Park would therefore be a tricky fixture for City at the best of times, but the timing, between the two legs of a Champions League quarter-final against Tottenham, adds an extra layer of difficulty.
Moreover, City's 1-0 defeat in the first leg in north London, means they are in danger of again missing out on the trophy that the club's Abu Dhabi owners most desire after billions of pounds worth of investment.
"That's true (it is a dangerous game)," said Guardiola. "We knew it from weeks ago, how it would be between these important games and Tottenham in the Champions League.
"Selhurst Park is always difficult, not just for the stadium itself but for the quality of the players they have."
Guardiola attracted criticism for what was seen as a conservative team selection against Spurs in midweek, leaving both Kevin de Bruyne and Leroy Sane on the bench until the final minute, while peripheral figures Fabian Delph and Riyad Mahrez started.
-- Upbeat attitude --
Guardiola's upbeat attitude, despite a first defeat in 15 games, suggests a longer-term plan to keep his squad as fresh as possible for a gruelling run-in.
After Palace, City host Tottenham twice in four days in the second leg of their Champions League tie and the Premier League.
Then comes a midweek derby at Manchester United and a trip to Burnley before potentially two more Champions League games in the space of a week in the semi-finals.
The title remains in City's hands, trailing Liverpool by two points but with a game in hand.
Yet, it is Jurgen Klopp's men who appear to have the easier run-in as they hope to end a 29-year wait to win the title, especially once Sunday's visit of Chelsea to Anfield is out the way.
That game kicks-off just minutes after the final whistle at Selhurst Park, making it all the more vital that City land a psychological blow by going back to the top of the table against Palace.
"We have six games left to finish the Premier League. We know what we are playing for and we are going to prepare well," added Guardiola.
Oleksandr Zinchenko and Bernardo Silva are back in contention are minor muscle injuries, but are likely to be kept in reserve and rested for Tottenham, with Danilo, Benjamin Mendy, Sane and De Bruyne among those set to return.