The students at St James Catholic High School in Cheadle Hulme are understood to have taken pills known as Teddy Bears on Tuesday, according to the Manchester Evening News.
Head teacher Tim Beesley told the newspaper: "We can confirm that there has been an incident this week where a small number of students have taken a recreational drug on their way to school - this is currently under investigation.
"Our substance abuse policy states that any student found in possession of drugs or alcohol, or engaged in supplying drugs or alcohol, may face permanent exclusion."
Greater Manchester Police said enquiries are ongoing and it appealed for anyone with information to call police or anonymously contact Crimestoppers.
A spokesman said: "Shortly before 4.45pm on Tuesday 28th February, police received a report of drugs issues at a school on St James' Way."
Head teacher Tim Beesley added: "Whenever we are made aware of any concerns regarding our students we have a duty of care to notify parents or carers, and offer whatever support we can, including agencies such as MOSAIC (Stockport Young Peoples Drug and Alcohol Service).
"We remain committed to enabling all students to study in a school environment entirely free of recreational drugs and the misuse of alcohol."