Paramedics were called to an address in Greasby at 1.45am on Wednesday following reports that the girl had collapsed.
She was pronounced dead at the scene and a post-mortem is due to take place.
A boy, also 14, was detained on suspicion of supplying or offering to supply an unspecified controlled drug, Merseyside Police said.
An 18-year-old male from Tranmere was later arrested on suspicion of possession with intent to supply controlled drugs.
Detective Inspector Paul Parry described it as a “terribly tragic incident”.
“People taking these drugs don’t know what’s in them, where they’ve come from or what effects they may have,” he added.
“We know that children sometimes use and share drugs, largely because they are afraid of taking them on their own, but they need to understand that passing a class A drug on to another child amounts to supplying.
“Other children also take them through peer pressure and parents need to reassure their children that it is the right thing to say no and resist this pressure as we wouldn’t want another family to go through what this young girl’s family are going through.”