Police were called to reports of an assault at a bar on Catalan Square at around 10.10pm on Friday night, Greater Manchester Police said.
A man in his 30s had been at Barca Club with his friends when another man walked past him and shouted abuse at a group of people in the bar.
Police said when the victim asked him to calm down, the offender turned to his friend and asked for the machete.
His friend brought over a backpack, which the offender pulled the machete out of, before turning and striking the victim's hand with it.
The man was taken to hospital where he is still being treated for life-changing injuries.
Police said the three offenders fled from the scene on foot and with a push bike.
Detective Inspector Mark Davis, of GMP's City of Manchester Division, said: "This man should be enjoying the rest of a well-earned weekend, instead he's in hospital being treated for injuries that will change his life.
"The way the offender pulled the machete out and brutally struck this innocent man without hesitation is chilling, and we will do everything we can to find the person responsible.
"If you were around Castlefield last night and saw either the assault, or know something that could help with our enquiries, please contact police and share this with us."
Anyone with information is asked to contact police on 101 or through Crimestoppers on 0800 555 111.