The City striker's previous Premier League game in May ended in memorable fashion as he fired home a stoppage-time winner against QPR to clinch City's first league title for 44 years.
But the Argentina international lasted just eight minutes of his side's opening match of this Premier League campaign before being stretchered off following a challenge from Southampton defender Nathaniel Clyne.
The 24-year-old received treatment for several minutes after collapsing to the turf in agony as he attempted to continue playing.
Mancini has confirmed the forward will undergo a scan to determine how long he will be out of action and does not want to speculate ahead of those results.
"I am worried," said the City boss. "Anything around the knee is dangerous and this injury was so strange.
"At the moment, we don't know. We need to wait for the scan in two days."
Aguero, who joined from Atletico Madrid last summer, scored 23 Premier League goals in City's title-winning campaign and his long-term absence would be a major blow.
Mancini is already frustrated having missed out on Robin van Persie, who joined Manchester United from Arsenal last week, and Aguero's injury could prompt action in the transfer market.
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