The pair were discovered at the hotel in Romford, Essex, at around 12.43pm yesterday afternoon.
They were both pronounced dead at the scene.
Specialist officers also attended after the substance was found.
The Metropolitan Police said the deaths were being treated as “unexpected” and investigations into the circumstances are ongoing.
A spokesperson for the force said: “Police were called at 12:43pm on Saturday, 1 July after two people were found unresponsive at a hotel in Mercury Gardens, Romford.
“A man and a woman were pronounced dead at the scene.
“Specialist officers also attended due to concerns about a substance that was found at the scene.”
A spokesperson for Premier Inn added: “Our thoughts are with the friends and family of these guests at this terribly sad time.
“Our team are assisting the police with their investigation.”