Carlo Ancelotti confirmed Everton will appeal Lucas Digne's red card, questioning whether the extensive coverage of Jordan Pickford's tackle on Virgil van Dijk last week played a part in the decision.
James Ward-Prowse and Che Adams did the damage at St Mary's on Sunday, as Premier League leaders Everton suffered their first defeat in all competitions this season.
Everton's 2-0 reverse means 2020-21 is the first English top-flight campaign since 1967-68 in which no side has gone unbeaten through the first six matches.
A year to the day since Southampton were thrashed 9-0 at home by Leicester City, Everton's hopes of a comeback were further diminished when Digne received a straight red card for a challenge on Kyle Walker-Peters in the 72nd minute.
Sprinting after Walker-Peters, Digne appeared to slow himself but in doing so stepped on the heel of the Southampton full-back, prompting his dismissal.
It is the first time since December 2002 that Everton have received straight red cards in back-to-back Premier League games, after Richarlison was dismissed in last week's Merseyside derby.
Earlier in that match, Pickford was fortunate to escape punishment for a tackle on Van Dijk that resulted in the Liverpool centre-back suffering a potentially season-ending knee injury – an incident that has been at the centre of a media storm since.
Ancelotti believes the reaction to the decisions in the Merseyside derby possibly played a part in Digne's dismissal at Saints, which left him fuming.
"It was a joke, the red card, because it was not intentional," Ancelotti told Sky Sports. "Maybe it can be a yellow but for sure it was not violent conduct. They could check it better.
"Maybe all the rumours, all week against Pickford, against Richarlison, affected the decision. If it is like this, it's not right, it's not fair. We are going to appeal, for sure."
Liverpool's Georginio Wijnaldum was critical of Everton after the derby and claimed Ancelotti's side were "unacceptable".
Everton received three red cards last season, though all were for second bookable offences, with the Toffees collecting 70 yellow cards in total – an average of 1.84 bookings per game.
This season, Ancelotti's team have received seven yellow cards and two straight reds from their six league matches, conceding 70 fouls (11.6 per match), which is a decrease from 12.4 per game in 2019-20.
If his red card is not rescinded, Digne will miss league matches against Newcastle United, Manchester United and Fulham.
Ralph Hasenhuttl took a different view, with Southampton's boss saying: "He tried before to kick him, finally he hit him from behind. It was a clear red card for me."