Aguero has 10 goals in 12 appearances across all competitions this season, during which time he has established himself as City's all-time leading goalscorer.
The Argentina star looked on as an unused substitute as Brazilian team-mate Jesus joined him in double figures for the campaign by opening the scoring in Sunday's (NZDT) 2-0 win at Leicester City, which preserved the Premier League leader's unbeaten record.
This run began with Guardiola using Aguero and Jesus in tandem but it is now a case of one or the other inside in-form wingers Raheem Sterling and Leroy Sane.
"For me it is so tough to leave Gabriel or Sergio out, so tough," the City boss said ahead of Tuesday's Champions League match against Feyenoord, where a better result than Shakhtar Donetsk manage at Napoli will guarantee top spot in Group F.
"But we play with just one striker and I have to change something. There are a lot of games and they have to be ready and prepare well, especially sometimes when they are on the bench and the situation is not good – be ready to try to win the game."
Guardiola made it clear his change of approach in attack is based solely upon losing full-back Benjamin Mendy to a knee ligament injury.
The former Monaco favourite made an instant impression at City with his lightning raids down the left flank, a factor that allowed Guardiola to select a narrow frontline.
Fabian Delph has deputised superbly for the absent France international over the past two months but does not provide the same kind of attacking threat, leaving Sane to supply the natural width.
"In that moment [when Aguero and Jesus played together] we had Mendy and when you have Mendy you [the left-back] play wide and the winger can go inside," Guardiola explained.
"Without Mendy, Delph cannot do that and you have to go wide with Sane. That is the only reason why they don't play together."
City has already qualified for the last 16, leading to speculation Guardiola could hand European debuts to highly rated youngsters Brahim Diaz and Phil Foden – the latter playmaker having seen his stock rise as a star performer in England's Under-17 World Cup triumph.
"They are two young players who I see in the training session every day they are ready," the former Barcelona boss added. "If not, they would not be training every day with us.
"They have to have quality to be with us. It is not to have fun and be gentle with the guys from the academy.
"The skills are there, the qualities are there. What we can help them with is the speed. The lack of time to think is quicker in our training sessions. Phil has to fight the duels with Fernandinho, Kevin De Bruyne and David Silva.
"They have had a lot of games and competitions coming up now and they have to be ready because sometimes a manager makes surprises."