Plymouth, who dispatched Liverpool in the previous round, were eyeing another Premier League scalp and briefly looked to be on their way to doing so through Maksym Talovierov's header in the first half.
The Ukrainian defender sent the travelling supporters into raptures, although the lead would last just a few minutes as 19-year-old O'Reilly levelled for City shortly before half-time.
That seemed to set City up to take the second half by the scruff of the neck, which they did, but Plymouth weathered the pressure for a good portion.
City, though, found another breakthrough courtesy of O'Reilly who found the net again on 77 minutes with a header to give Pep Guardiola's side the lead.
The go-ahead goal seemed to deflate the visitors and the final City blow was landed when Erling Haaland – on as a second-half substitute – drilled across a ball for Kevin De Bruyne to tap in.
Bournemouth also reached the last eight for just the third time in their history after winning a penalty shootout 5-4 against Wolves after an action-packed 1-1 draw.
Evanilson opened the scoring for the Cherries before Milos Kerkez had a goal disallowed after an eight-minute VAR check, with the new semi-automated offside technology at the Vitality Stadium going down.
Matheus Cunha rifled in an equaliser for Wolves to force extra time, although his part in the game would end just before penalties after being shown a straight red card for a scuffle with Kerkez.
Bournemouth's Dean Huijsen missed the shootout's first kick, giving Matt Doherty the chance to send Wolves through, but he rolled his effort wide.
Boubacar Traore then hit the crossbar, allowing Luis Sinisterra to step up and confirm Bournemouth's name in the hat.
Mateta hospitalised in Palace win
Crystal Palace advanced with an assured 3-1 win over 10-man Millwall at Selhurst Park, although victory was marred by a nasty injury to Jean-Philippe Mateta.
Mateta was stretchered off after being caught in the head by a high boot from onrushing Millwall goalkeeper Liam Roberts, who received his marching orders just eight minutes in.
After nearly 10 minutes of on-field treatment, the French forward was taken to hospital, where he later provided an update to say he was "doing well".
Palace capitalised on the man advantage by forcing a Japhet Tanganga own goal before Daniel Munoz added a second.
Wes Harding pulled one back for Millwall in first-half stoppage time, but Palace sealed their place in the next round when Eddie Nketiah headed home on 82 minutes.
Elsewhere, Milutin Osmajic taunted the Burnley fans after scoring to help Preston to a 3-0 triumph and reach the quarter-finals for the first time since 1966.
The tie between the Championship rivals was overshadowed by Osmajic being accused of racially abusing Burnley's Hannibal Mejbri during a league meeting at Deepdale a fortnight ago.
Hannibal was left out of the squad by Scott Parker while Osmajic, who rejects the allegations, started for Preston and scored their second goal before cupping his ear toward the Burnley supporters.
Robbie Brady and Will Keane scored either side of the Montenegrin's tally to send a rotated Burnley side crashing out.