Martin O'Neill's frustrations increased at Sunderland after a shock defeat by Bolton Wanderers in their FA Cup third round replay while Queens Park Rangers knocked out West Bromwich Albion.
Elsewhere, Stoke City and Fulham both needed extra time to overcome Crystal Palace and Blackpool, respectively, Wigan Athletic avoided an upset at Bournemouth, and Leeds United booked a home date with Tottenham Hotspur in the fourth round after fighting back at Birmingham City.
Brentford set up a dream derby with Chelsea having defeated Southend United, MK Dons knocked out Sheffield Wednesday, and Hull City beat Leyton Orient after extra time.
Sunderland's disappointing season hit a new low as O'Neill's team slumped to a 2-0 defeat by Bolton on a miserable night for the home team at the Stadium of Light, where Marvin Sordell scored a penalty and a second goal inside the final half-an-hour.
In their fourth meeting in as many months, QPR eliminated Premier League rivals West Brom at The Hawthorns, where striker Jay Bothroyd scored the only goal of the game and visiting goalkeeper Robert Green produced a heroic performance in a 1-0 win.
Stoke required extra time to see off Crystal Palace but two goals in the additional half-an-hour from Jon Walters, who atoned for two own goals in Saturday's heavy league defeat by Chelsea, helped eventually secure a flattering 4-1 win and lined up a fourth round repeat of the 2011 FA Cup final against Manchester City.
Having been held to a draw at the DW Stadium in the original tie, Wigan made no such mistake in a 1-0 win which ended lower league Bournemouth's long unbeaten run thanks to Mauro Boselli's eye-catching 18th minute goal.
Brede Hangeland saved Fulham manager Martin Jol from increased pressure as the captain's header deep into extra time grabbed a 2-1 win at managerless Blackpool after Kieran Richardson's 90th minute equaliser had rescued the Premier League club from defeat in normal time.
Leeds scheduled a repeat of their 2010 FA Cup fourth round meeting with Premier League Tottenham as a Ross McCormack goal and a penalty from El-Hadji Diouf produced a second-half turnaround in a 2-1 win at Birmingham.
League One Brentford booked a West London derby with the Premier League elite of Chelsea following a 2-1 win over Southend courtesy of goals from Paul Hayes and Clayton Donaldson at Griffin Park.
MK Dons did not allow the speculation surrounding their manager, Karl Robinson, and a potential move to Blackpool act as a distraction as they proved too strong for Championship Sheffield Wednesday in a 2-0 home win to reach the fourth round for the first time in their history.
After conceding an injury-time equaliser to force a replay in the first tie, Leyton Orient again suffered late heartbreak at the hands of Hull as Tom Cairney's extra-time goal just three minutes from a penalty shoot-out earned a 2-1 win and saw the Championship club through.