Police have issued a warning to youngsters after the four boys were taken ill in Doncaster over the weekend.
Officers said they were contacted on Saturday about the four admissions.
A spokesman added that all the teenagers have since been discharged from hospital.
He said a 16-year-old boy has been arrested on suspicion of supplying intoxicating substances to under-18s in connection with the incidents. He has been released on bail pending further inquiries.
The spokesman said South Yorkshire Police and and other agencies working with them have become aware of the increasing availability, use and potential harms caused by so-called legal highs.
Sergeant Carl Lindley said: “People think that because a substance is legal it will be safe.
“However these substances are packaged and labelled as ‘not for human consumption’ to get round the strict laws that protect the public with the sales of medicines or even food.
“This means there is no quality control and the exact ingredients vary in each package.
“The chemical composition of these substances is similar to that of controlled drugs and can have equally serious effects.
“The inherent dangers of taking these unknown and untested chemicals are obvious, yet, because of the relatively low cost and ease of access, people are still tempted to experiment.
“It is important to note that mixing these substances or taking them with illegal drugs or alcohol massively increases the risks.
“In Doncaster, we have developed a multi-agency approach to this issue.
“We are working with partner agencies such as social services, trading standards and public health to educate young people as well as gathering information on people selling these substances.”
Assistant director of Doncaster Council public health Dr Rupert Suckling said: “It is concerning to hear that four young people have been hospitalised following the use of novel psychoactive substances (NPS).
“We discourage the use of these substances, and are committed to doing everything we can to tackle this difficult problem using the powers at our disposal. We have worked hard to tackle the use of NPS in Doncaster, in partnership with South Yorkshire Police, Doncaster Trading Standards and others.
“Ultimately, our powers to act are limited by legislation, and this is an issue for Government to address.”