Townsend's incredible 30-yard strike put Palace 2-1 up at the Etihad Stadium with Roy Hodgson's side eventually coming through 3-2 to inflict a first home defeat on City in the Premier League this season.
Aguero, who replaced Nicolas Otamendi as Guardiola chased the game at 2-1, and De Bruyne started the midweek Carabao Cup triumph at Leicester City following recent lay-offs, while Guardiola watched John Stones turn in a mixed performance at the base of his midfield in Fernandinho's injury-enforced absence.
A key figure in City's record-breaking Premier League campaign last season and England's run to the 2018 FIFA World Cup semi-finals, Walker looked to be running on empty as he was at fault for the two avoidable Palace goals.
Townsend will rightfully hog the headlines but Wan-Bissaka did much to enhance his burgeoning reputation, keeping the in-form Sane on a short leash and making a succession of courageous challenges.
But Palace trailed for just six minutes as they surprised City by pushing back.
One social media user even went as far as to claim they would name their newborn baby after the player should Palace win the game. Subs: Aguero 5, De Bruyne 7, Mahrez 5.
The defeat was City's second in three league games and handed the title initiative to Liverpool.
He said: "The third goal, the penalty, was really tough for us".
And City were hit for six three minutes later when Andros Townsend scored a contender for goal of the season.
"When you have a lot of games, everyone has to play".
The early signs suggested that it would be another comfortable afternoon for City, who had won 10 of their last 12 Premier League matches against Palace overall and 10 in a row on home soil in all competitions ahead of this latest tussle.