Firefighters were called to a blaze at a semi-detached home in Boulton Avenue, West Kirby, at 01:24 GMT on Monday.
The man was pronounced dead at the scene and the woman was taken to Arrowe Park Hospital where she later died. The next of kin have been informed.
A Merseyside Police spokeswoman said: "Our investigation is ongoing, but at this stage the indications are that it is not suspicious."
Police have not released the names or ages of the victims as formal identification has yet to take place.
Merseyside Fire and Rescue said engines from Upton, Kirkdale and Kensington tackled the fire.
A man and a woman have died in a house fire in Merseyside.