The 20-year-old started on the left-hand side of the champions' backline at Selhurst Park, where City got off to the worst possible start as Daniel Munoz put the Eagles ahead inside four minutes.
Lewis left Munoz exposed as he tried to catch the Colombian offside, unaware that Kyle Walker was keeping Munoz level, although Erling Haaland restored parity for Pep Guardiola's team on the half-hour mark.
The Premier League holders found themselves behind again early in the second half, though, as Maxence Lacroix rose highest to head home a Will Hughes corner, before Lewis's terrific finish into the top corner denied Palace what would have been a merited win.
The England international was booked not long after his strike for dissent, and he then had to take the walk of shame for a perceived challenge on Trevoh Chalobah as the game drew to a close.
Lewis out of Man United game after Palace sending-off
There was fierce debate over whether Chalobah had fouled Lewis or if the Man City defender caught the Palace man unfairly, and on-field referee Rob Jones deemed the 20-year-old to be at fault.
As the VAR room cannot intervene when it comes to second yellow cards, Man City had no choice but to see out the final few moments with 10 men, and Lewis has now picked up a one-match domestic ban.
The versatile defender will serve that punishment when Man United pay a visit to the Etihad on December 15, although he will be free to take on Juventus in the Champions League on Wednesday.
Both Guardiola and Man City's players let referee Jones exactly what they made of Lewis's dismissal at the full-time whistle, as the champions' hopes of retaining their crown suffered another potentially fatal blow.
The Citizens are now eight points below leaders Liverpool, who have a game in hand on Guardiola's side after their Merseyside derby with Everton on Saturday was postponed due to Storm Darragh.
Who could replace Lewis against Man United?
Lewis's ban only exacerbates City's selection crisis at the back, as Guardiola was already without John Stones, Nathan Ake and Manuel Akanji for the clash with Oliver Glasner's side this weekend.
Stones (foot) and Ake (thigh) do not appear to be in with good chances of making their comebacks in the derby, although Akanji's issue is not so severe, so the Swiss defender could very well step in for Lewis next weekend.
Akanji, Ruben Dias, Walker and Josko Gvardiol could form City's backline for the visit of Ruben Amorim's team, and Lewis will be back for the trip to Aston Villa on December 21.
Rodri, Oscar Bobb and Mateo Kovacic are also expected to miss the Manchester derby next weekend due to injury, but Phil Foden will push to return from illness against either Juventus or the Red Devils.
Written by
Ben Knapton