Holders Arsenal crash out of FA Cup as West Ham cruise
The Gunners, who have won the competition a record 14 times, went down 1-0 on England's south coast courtesy of a Gabriel own goal.
Brighton edged past Blackpool and Sheffield United beat Plymouth as the other Premier League teams in action avoided embarrassment against lower-league opposition.
In the early kick-off at St Mary's Stadium, Arsenal paid the price for a sluggish start against fellow top-flight side Southampton.
Arteta made seven changes from his team's 3-0 league win against Newcastle on Monday, with Pierre-Emerick Aubameyang and midfielder Emile Smith Rowe both absent.
Southampton's James Ward-Prowse rattled the crossbar from a swerving corner and Che Adams forced a fine save from Arsenal goalkeeper Bernd Leno.
The 1976 FA Cup winners reaped the reward their positive approach deserved in the 24th minute.
Mohamed Elneny gave away possession on the edge of his own box and the ball was worked to Kyle Walker-Peters on the right.
The defender drilled the ball across the six-yard area and it was turned in by Gabriel -- the first time rejuvenated Arsenal had conceded for 508 minutes.
Arsenal improved in the second half. They went close through Eddie Nketiah's deflected shot and Alexandre Lacazette was inches away from connecting with a cross from fellow substitute Bukayo Saka but they could not find an equaliser.
"We had a dream to do it again like last year and the dream today is over," he said.
"I am as well disappointed with the way we conceded the goal in an area where we know we shouldn't be doing that. At the same time I cannot fault the effort of the players."
Southampton boss Ralph Hasenhuttl, who welcomed back Danny Ings after a hamstring injury and a positive coronavirus test in a strong line-up, was delighted with the win.
"We had in the first half more punch and more power," said the Austrian, whose side briefly topped the Premier League earlier this season.
"In the second half it's normal they have a lift.... In general our work without the ball was good. It was a good team performance today."
Pablo Fornals gave impressive West Ham an early lead at home to Doncaster as they dominated the League One side from the kick-off.
The home side doubled their advantage later in the first half when Andriy Yarmolenko pounced.
An own goal early in the second half from Andy Butler made it 3-0 and Oladapo Afolayan completed the rout.
West Ham, seventh in the Premier League after three straight wins, will play either Manchester United or Liverpool in the next round.
But Brighton did not have it all their own way against League One team Blackpool.
They went 1-0 ahead in the 27th minute courtesy of a thunderous strike from Yves Bissouma but were pegged back in first-half stoppage time by a Gary Madine goal.
The home side restored their lead in the 58th minute when Alexis Mac Allister's shot from distance took a significant deflection off Steven Alzate and beat Blackpool keeper Chris Maxwell.
Goals from Chris Basham and Billy Sharp were enough for Premier League strugglers Sheffield United to see off League One opponents Plymouth.
Elsewhere, Swansea thumped fellow Championship side Nottingham Forest 5-1, while Bristol City beat Millwall 3-0.
Barnsley beat Championship leaders Norwich 1-0.
Manchester City travel to fourth-tier Cheltenham in the evening kick-off on Saturday.
On Sunday, Premier League leaders Manchester United face Liverpool in the tie of the round while Chelsea are in action against Luton.
Sixth-tier Chorley put up a brave fight against Premier League side Wolves on Friday but lost 1-0.