Southampton have lost by nine goals in each of the last two seasons -- to Leicester City in 2019 and to Manchester United in February -- but ahead of their visit to the Etihad Stadium on Wednesday, Guardiola reacted angrily to a suggestion it could happen again.
"The score will be 18-0 -- what a question," Guardiola said on Tuesday at a news conference when asked if Southampton's two 9-0 defeats would be in his mind ahead of the game.
"They [Manchester United] scored nine because it was 89 minutes 10 vs. 11 -- you think it's a joke? Come on, we'll try to win the game, that's all and get the three points.
"I'm a big fan of this team and the way they play. I see the quality of what they do and it's another test to play good and try to win."
City are looking to bounce back after their 21-game winning run ended with a 2-0 defeat to Manchester United on Sunday.
Despite the setback, City are still 11 points clear at the top of the table with 10 games to play but Guardiola still believes they can be caught.
"When the option is open everything can happen," Guardiola said. "For the people like United they can do it. There are 10 games left and we have to win six or seven [to win the title] and we'll try to win the first one [against Southampton].
"In the Premier League it's so complicated, so difficult. It's so difficult to realise what we've done. We've a lot of work to do to arrive in the last games in contention to win the Premier League."
Guardiola, who hinted he could recall Sergio Aguero and Phil Foden to the starting XI after both were named as substitutes against United, did not watch a tape of the derby defeat, instead preferring to prepare for Southampton.
The City boss said after the "sadness" of losing to United, his players were "on fire" in training on Tuesday morning as they warmed up for Southampton.
"It was a mix of disappointment and sadness," he said. "The second day [Monday] was better and today [Tuesday] completely on fire.
"It's a normal process when you lose the games. The reaction is common. We lost the game but everyone realises how difficult to win games and do good runs. Just think of the next one."
Meanwhile, City will play Borussia Monchengladbach in the second leg of their Champions League round-of-16 tie in Budapest, after the game was shifted to a neutral venue, UEFA said on Wednesday.
The match is the latest to be affected by COVID-19 travel restrictions in Europe and will now be held on March 16 at the Puskas Arena, UEFA added.
The game was originally scheduled for City's Etihad Stadium, and the first leg in Germany was also shifted to Budapest on Feb. 24.