Arsenal's inability to break down Championship leaders Hull's massed defences ended their 14-match winning streak in the competition.
Top-flight Watford were also up against Championship opposition in Leeds United and edged a dour game 1-0 to reach the quarter-finals for the first time in nine years.
In the day's only all-Premier League clash, Everton won 2-0 at Bournemouth, Ross Barkley and Romelu Lukaku scoring for the visitors after the Toffees' keeper Joel Robles saved a first-half penalty from Charlie Daniels.
Reading, currently 16th in the second-tier Championship, guaranteed there will be at least one club from outside the Premier League in the last eight as they came from behind to beat West Brom.
They have won only once in the league since the turn of the year but goals from Paul McShane, Michael Hector and Lucas Piazon punished West Brom for a lacklustre display after they had taken the lead through captain Darren Fletcher.
Both McShane, a former West Brom player, and Hector converted headers from free kicks by Oliver Norwood while Piazon's late effort capped a dismal exit for West Brom.
It only got uglier for Albion after the final whistle when their midfielder Chris Brunt was struck by a coin thrown from an area housing West Brom fans.
"I've never seen anything like that in 10 years, it's disgusting," Brunt said in a statement. "I hope the police have got hold of him."
Arsenal's three-year unbeaten run in the FA Cup continued but they laboured to beat a second-string Hull side.
With one eye on Tuesday's Champions League last 16 first leg at home to Barcelona, Arsenal made nine changes from the side that beat Premier League leaders Leicester City last week.
Even when manager Arsene Wenger, in charge of his 100th FA Cup tie for the club, threw on the likes of Alexis Sanchez and Olivier Giroud the Gunners could find no way past Hull's inspired keeper Eldin Jakupovic.
The Gunners now face a testing replay to keep alive their hopes of becoming the first club to win the Cup three times in succession in the modern era.
"The goalkeeper did well of course, but we had maybe 70 per cent possession and more than 20 shots on goal, and we didn’t score," Wenger told reporters.
"The replay is not especially good news but Hull defended very well. Between that and going out, we choose the replay."
GREAT SAVES
The closest Arsenal came to breaking the deadlock was Joel Campbell's 54th-minute free kick that was tipped against the post by Jakupovic who also denied Theo Walcott and Sanchez.
Hull, beaten by Arsenal in the 2014 FA Cup final after leading 2-0 inside the opening 10 minutes, had one chance when David Meyler shot into the side-netting.
Hull manager Steve Bruce, whose priority is promotion to the Premier League, defended his weakened lineup which included a place for 16-year-old Josh Tymon.
"It's not like I sent out a team of kids," Bruce said.
"We made 10 changes and we rode our luck a bit, but the team deserved it for the spirit and effort they gave."
Premier League Watford avoided an upset against former winners Leeds when Scott Wootton's own goal proved decisive at Vicarage Road.
On Sunday, the standout tie of the round sees Chelsea host Manchester City while Tottenham Hotspur play Crystal Palace in another top-flight duel.
(Editing by Ed Osmond and Ian Chadband)
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