Saints began the season as the toast of English football, with their blend of home-grown talent and big-money signings impressing in an attractive, high-tempo style.
Not only that, they were also getting results and could have gone top of the Barclays Premier League with victory at Arsenal two weeks ago.
However, Saints have slumped to eighth after a run of three successive defeats and now face the unenviable task of attempting to thwart in-form City.
That challenge has been made all the more difficult by injuries picked up by Victor Wanyama and Nathaniel Clyne in the midweek defeat to Aston Villa, swelling the possible first-team absentees for the game to eight.
"I believe that every game is a test, not just against Manchester City," the Argentinian said ahead of Saturday's match. "Every single game is a very large test for us.
"It is clear that we picked up some injuries against Aston Villa that we did not have in the past, but nothing has changed within this team.
"This team still believes, it still believes in how we play, and what a great chance for us to go and invert this negative run we are on in front of our fans in a great stadium. This is a very good chance for us to change our fortunes right now."
Such positivity will surprise many onlookers given some of the names on Southampton's injury list.
Wanyama and Clyne are joined on the sidelines by Morgan Schneiderlin, Guly do Prado and Danny Fox, while Jose Fonte, so impressive at centre-back alongside Dejan Lovren, is a doubt.
Third-choice goalkeeper Paulo Gazzaniga will again deputise in goal as Artur Boruc fractured his hand last week and back-up Kelvin Davis is struggling with a side injury.
It makes a result like February's 3-1 defeat of City - the first victory of Pochettino's reign - look a tough ask, yet he is confident in the strength in depth at his disposal.
The Saints boss has already named 12 players from the youth system in the matchday squad this season and believes harnessing young talent will be key moving forwards.
"I am confident that we can overcome this bad run that we are on," Pochettino said. "That is what we are working for.
"The project in Southampton is to mix very young players with a lot more experienced players.
"This is a big test for us right now and it also gives us a good chance to bring some of the younger players, such as Harrison Reed, Sam Gallagher, Cody Cropper, Matt Targett, Will Britt.
"It is a very good experience for them to be in the mix with more veteran players in the senior side. It is a very good chance for us to execute that plan to bring younger players into the side."
Most of those young players will only make up the numbers for now, with Adam Lallana, James Ward-Prowse, Luke Shaw and Calum Chambers the only academy graduates likely to start against City.
It is a match that not only gives Saints the chance to get back on track, but for former Espanyol manager Pochettino to get one over on old foe Manuel Pellegrini, a man he knows well from his time in Spain.
"I have many memories of having faced Manuel Pellegrini in La Liga, when he was Villarreal, Malaga and Real Madrid," he said.
"I even knew him when I was with Under-18s in Argentina. He was managing the Chile Under-20s some 25 years ago.
"I have great respect for him. I wouldn't say that we were friends, but we have a great working relationship and he is someone I admire. We have a very good professional relationship."