The 17-year-old girl died on Monday after it is thought she suffered an adverse reaction to a form of the drug known as Mastercard, police said.
She had been on a night out at the Victoria Warehouse in Trafford.
A man, 19, and woman, 20, are being held on suspicion of possession with intent to supply a Class A drug.
They were arrested in the St Helens area early on Tuesday morning and will be questioned later, Greater Manchester Police said.
The young woman died in hospital after police were called to the Victoria Warehouse shortly after 05:00 BST.
Det Ch Insp Ben Ewart said police "sadly" know "that other people will have taken this form of ecstasy" and urged anybody who may have taken it to "get themselves checked out."
"Our thoughts and condolences remain with the family of this girl at this heart breaking time," he said.
He asked anybody who knows where the drug may have come from to contact police.
Two people have been arrested in connection with the death of a teenager after she took ecstasy on a night out.