The outbreak was first reported this month in the United Kingdom - which has registered 111 cases, mostly in children under 10 - and has since been identified in at least 12 countries.
Forty cases have been recorded in the European Union and European Economic Area, ECDC director Andrea Ammon told reporters in a virtual briefing.
The United States and Israel have also registered cases.
The ECDC is investigating alongside individual countries' authorities and the World Health Organisation.
Severe hepatitis, or inflammation of the liver, is rare in otherwise healthy children.
Unusually, the new cases do not feature the viruses typically responsible for acute liver inflammation - hepatitis A, B, C, D and E.
According to the WHO, 17 children have needed liver transplants as a result of the recent cases and one has died.
Ammon said the investigations so far pointed towards a link to infection with an adenovirus, a family of common viruses that can cause flu-like or gastrointestinal symptoms.
She said a theory that COVID-19 lockdowns may have weakened children's immunity, because they were less exposed to common pathogens while in isolation, was one of several being considered.
Scientists are also investigating whether the adenovirus involved has mutated, or is acting in tandem with another infection, possibly COVID-19.
A toxin could also be responsible but this is thought less likely due to the geographical spread of the cases reported.
Any link with COVID-19 vaccination has been ruled out as the children had not been immunised.
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