Guardiola must decide how many of City's best players to risk for at the Riverside Stadium as they have a crucial Champions League last 16 second leg clash with Monaco four days later.
The FA Cup offers the more realistic prospect of Guardiola's first trophy with City, but the Spaniard's success in Europe was a key factor in the decision to bring him to Manchester last year.
The former Barcelona and Bayern Munich boss will find his skills tested to the limit in what is a defining week for City's season.
Guardiola lauds Bravo despite criticism from fans
His most recent attempt at squad rotation failed when Guardiola decided to start Wednesday's Premier League home game against Stoke without his two best creative players.
David Silva was named as a substitute and Raheem Sterling was rested altogether as City drew 0-0, leaving them 10 points behind leaders Chelsea.
Guardiola has rested players for each of City's FA Cup games so far, but there are signs that he is taking the competition more seriously the further he progresses.
Having made eight changes for their goalless fifth round tie at Huddersfield last month, he made only four for the replay, which City won 5-1.
Guardiola praises 'mentally stable' City after eight-goal thriller against Monaco
Claudio Bravo, now the second-choice goalkeeper for league games, has come back in for the last two FA Cup ties and should play again at the Riverside Stadium, while full-back Pablo Zabaleta has also tended to be used in the competition.
Perhaps the biggest question revolves around Sergio Aguero.
The Argentina striker was demoted to the bench following the January arrival of Gabriel Jesus from Brazilian club Palmeiras.
Yet since Jesus broke his foot against Bournemouth on February 13, Aguero has proved indispensable.
He scored twice in 5-3 first leg win against Monaco, and is City's best hope of the away goal they may well need in the principality to secure European progress.
Guardiola cannot afford an injury to the striker, and so may decide to field Kelechi Iheanacho against Middlesbrough instead.
Guardiola rules out Barcelona return
City midfielder Yaya Toure hinted that there will be some changes on Saturday, saying: "We've got two games now where we need all the players. We have to try to do the business. Middlesbrough is going to be a tough, tough game.
"They've had a rest for a week. We'll try to do our best. Of course, one trophy would be very welcome for us."
Lincoln hoping for Gooner support
Non-league Lincoln City are hoping a strong start in Saturday's FA Cup quarter-final at Arsenal will help turn the Premier League club's divided fan base against the home team, defender Luke Waterfall has said.
Arsenal crashed out the Champions League at the first knockout stage for the seventh year in a row this week after losing 10-2 on aggregate to Bayern Munich, with a section of the club's fans calling for manager Arsene Wenger to resign.
Wenger has been in charge for the past 20 years and Waterfall said fifth-tier Lincoln might find unexpected support from disgruntled Arsenal supporters.
"Some Arsenal fans might be going there wanting us to win. If we start well, we might have 60,000 people behind us, not just 9,000 [travelling Lincoln fans]," the 26-year-old told British media.
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