Police officers were called to Salford Precinct last night following reports three children had taken pills.
They were rushed to hospital, where two are in a serious condition and one is under observation.
Greater Manchester Police is investigating how the girls got hold of the drugs, known as "Teddy Tablets".
Last month, a 17-year-old girl died in Greater Manchester after suffering an adverse reaction to ecstasy. Two people arrested in connection with her death are on bail.
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Detective Chief Inspector Chris Walker said: "Sadly, three more young people, who are only 12-years-old, have taken ecstasy and ended up in hospital.
"It outrages me that people think it is acceptable to sell controlled drugs to anyone, let alone 12-year-old girls.
"It is imperative young people understand the implications and avoid taking drugs, to stop any more young people ending up in hospital."
It is thought the girls are among the youngest people in the UK to have fallen ill after taking the drug.
He added the force would continue to warn people of the dangers of taking drugs.