Police said four youths in Crosshill Street in Moss Side were attacked by a gang at about 20:30 BST on Tuesday.
The teenager died in hospital while two 17-year-olds and an 18-year-old remain in hospital with serious injuries.
Police said there was no evidence to suggest it was linked to the conviction of a gang earlier that day for a separate murder in Moss Side.
A Greater Manchester Police spokesman said parts of Moss Side have been cordoned off while officers conduct their investigation and there would be extra patrols in the area over the next few days.
Supt Dave Pester said: "We completely understand that the community will be concerned after waking up and hearing this tragic news this morning.
"I want to assure you we have had officers on the ground working solidly through the night trying to get to the bottom of what has happened."
He said the force was in the "very early stages" of the murder investigation and trying to "understand the motive behind this attack and who is responsible".
Supt Pester added: "I want to make it clear, at this stage, there isn't any information to suggest this stabbing is linked to a murder trial which finished at Preston Crown Court yesterday."
An 18-year-old man has been stabbed to death in a "large fight" in Manchester, prompting a murder investigation.