Liverpool and Tottenham Hotspur have been given scares, before eventually beating lower-league sides in the FA Cup third round, while West Ham United ousted Leeds United in an all-Premier League clash.
Liverpool came from a goal down to win 4-1 against third-tier Shrewsbury Town, while Tottenham left it late before fighting back and then pulling away to beat Morecambe 3-1, with a battling display in the second half.
David Moyes' West Ham won 2-0 against Leeds, who were without 10 first-team players, including striker Patrick Bamford, but Arsenal won't add to their record 14 knockout championships this year, after falling to Nottingham Forest.
Liverpool midfielder Fabinho scored twice, including a first-half penalty, while Kaide Gordon and Roberto Firmino also found the scoresheet for the Merseyside club at Anfield.
"When you get the first goal against you, so many things can happen, but I liked the way we responded," says manager Juergen Klopp, who returned to the touchline, after his recovery from COVID-19.
Shrewsbury's Daniel Udoh put the visitors ahead in the 27th minute, after he slid in Nathanael Ogbeta's cross to score from close range, but Liverpool winger Gordon found the equaliser seven minutes later with a calm finish.
Brazil international Fabinho scored a penalty before halftime, sending Shrewsbury keeper Marko Marosi the wrong way, before Firmino added the third in the 78th minute, with a brilliant back-heel effort from close range.
Fabinho doubled his tally in the 93rd minute, blasting the ball into the roof of the net from a tight angle.
Tottenham's Harry Kane and Lucas Moura scored late to complete a comeback for Antonio Conte's team, who were greeted with a huge chorus of boos from fans, after a disappointing first-half performance.
Battling relegation in League One, Morecambe stunned their Premier League opponents, when Anthony O'Connor scored in the 33rd minute.
Tottenham paid the price for sloppy defending, as O'Connor side-footed a volley into the net from Morecambe's first corner of the game.
After a string of chances, Tottenham finally levelled in the 74th minute through Harry Winks, when he swung in a direct free-kick from the left touchline.
The hosts hit the front nine minutes later, when Moura strode into the box and rounded keeper Trevor Carson, before Kane wrapped up the win, after being smartly picked out by Giovani Lo Celso.
"For sure, we struggled a lot in the first part of the game and conceded a goal from the set-piece," says Conte.
"We deserve to win because, in these type of games, you have to show your strength. They defended with 11 players and that's normal in these games, but it is important to find the right solution."
West Ham defeated Leeds 2-0, after Manuel Lanzini scored the opener from close range in the 34th minute and Jarrod Bowen scored in the final minute of stoppage-time from Michail Antonio's pass.
Arsenal's hopes of winning a record-extending 15th FA Cup were sunk at the first hurdle, as they went down 1-0 at Championship side Nottingham Forest.
Substitute Lewis Grabban stretched out his leg to convert Ryan Yates's cross in the 83rd minute at a vibrant City Ground.
Arsenal were lacklustre and could have few complaints against a well-organised Forest side, who earned a Midlands derby against Leicester City in round four.
Arteta's side, who face Liverpool in the League Cup semi-final first leg next week, failed to even muster a shot on target, as they suffered a repeat of their third-round exit to Forest in 2017/18.
Wolverhampton Wanderers won 3-0 against Sheffield United, with two goals from Daniel Podence and another from Nelson Semedo, while Norwich City defeated Charlton Athletic 1-0 with a second-half goal from Milot Rashica.
Stoke City beat Leyton Orient 2-0, Luton Town thrashed League Two Harrogate Town 4-0 and Cardiff City defeated Preston North End 2-1 in extra time.