Guardiola’s side faces a side that knocked league leaders Liverpool out in the last round. City will need to be careful not to slip up like the Reds. With little chance of winning the league, City will likely go all out in the FA Cup as they chase their last shot at silverware.
The Spanish head coach firstly skipped questions on the news that La Liga president Javier Tebas has reported Manchester City to the European Commission for alleged breaches of rules relating to state-owned companies.
Eventually, he was asked whether Plymouth was an unknown in the competition and referred to their victory against Liverpool.
"It is not unknown. If you are able to beat the best team in the country this season, Liverpool. They went unbeaten also at Brentford then it is not unknown."
He was then questioned on whether talented youngster Oscar Bobb is ready to return from injury after he had a promising pre-season, only to suffer a broken leg on the eve of the campaign.
"He is getting better training yesterday and today as well but have been (out) longer than we expect but hopefully he can finish his part and can help us in the last part of the season. We want to help him desperately. It is a tough period for him but always there is light at the end of the tunnel. Always has been like that in life - sport especially."
The City boss then said that new signing Vitor Reis was in contention to start and stated that he is a long-term player that he is pleased with how he is adapting at the club so far.
"He is young, he came from Brazil. He has incredible focus. Defenders there have great physicality and conditioning, but also are so clever and intelligent, and this is one of the ones. He does not come for a short period, he comes for a long, long time. We are really pleased for the way he is training and behaving and the potential that he has."
One journalist did get an answer to the wider question of why Manchester City are a target for other people such as Tebas despite Guardiola avoiding the subject earlier.
"I don't know. It happened in the past with Uefa and in a few weeks it'll happen in the Premier League, the sentence (to the 115 charges), right? We wait, and after we talk."
Guardiola then spoke on the club's recent success and whether older players such as Kevin de Bruyne will be part of their future once the season ends.
"Never impossible but it is difficult because when you have done what we have done it was deemed impossible before we did what we have done. There are players here that their age is over 30 but they are part of the future of this club. Except Kevin (de Bruyne), and Kevin and the club will decide on his future everyone who has a contract for next season I expect him to be here. They are going to help us. Next season will be a lot of games. We cannot do it just with our new ones. They will be able to help and be part of our season."
He also opened up on whether Claudio Echeverri will feature in the first team this season after he arrived at the club this week after completing his switch from River Plate.
"I don't know. He arrived with two months left in the season and every game is a final for us. Now are are fourth but if we don't get results we are sixth or seventh. We lose one or two games right now we go down to eighth. When things are so tight every game is a final.
"We have two games in the Premier League before the international break that are massively important - because Nottingham (Forest) are third and Brighton are up there and making an incredible run.
"The focus is on that. We have long weeks to train and prepare well. Everyone must focus - the players first and me second.
"After the season we have done in the Premier League and Champions League, anyone cannot say much, cannot complain. To be focused is what the team needs and what the club needs and this is the most important thing right now."
Finally, Guardiola went into depth about why the Plymouth would be a "tricky" opponent this weekend despite many claiming it would be an easy game for the Premier League side.
"They defend really aggressive up front. They allow you to go outside then after it is like a trigger, they make an incredible movement - the wing-backs jumping and the defenders to win the ball in the transitions that they do.
"And with the attacking midfielders they have inside, they link really well with the strikers.
"In the Championship, League One, League Two the set-pieces are the main thing that I think the Premier League learn from this type of league.
"They are solid and, of course, since the manager took over the results are there. They only lost a few games in their last 10 or 11 so yes, I expect a difficult game.
"We play at home - that is a little advantage compared with away. But these types of games we know they are tricky because these types of teams, what they do, they do really well.
"When they can apply it and do better (at it) than we want to do then you are in trouble."