The fire broke out at around 2am at a home on Bushbury Lane in Oxley, Wolverhampton.
Residents recalled how they were woken by shouting, before seeing and smelling smoke billowing from the house.
Some tried to rescue the trapped men but were forced back by the flames, before fire crews arrived and got them out.
West Midlands Police said that its thoughts were with the families of the men who had passed away:
"A man was confirmed dead at the scene and another man passed away in hospital later.
"We've worked alongside fire service colleagues to assess the likely cause of the blaze. Following these enquiries we're not treating the fire as suspicious.
"We'll be preparing a full report for the coroner.
"Our thoughts are with those who’ve tragically lost ones today," a spokeswoman said.
West Midlands Ambulance Service sent three ambulances, three paramedic officers, Hazardous Area Response Team (HART) paramedics and a MERIT Trauma doctor and critical care paramedic to the scene. A spokeswoman said crews arrived to find firefighters rescuing two men from the house.
"The two men were in a critical condition and ambulance crews immediately commenced advanced treatment on scene," she said.
"One man was conveyed on blue lights to New Cross Hospital in a serious condition for further emergency care. Sadly, despite the best efforts of ambulance staff and fire colleagues, nothing could be done to save the second man and he was confirmed dead on scene.”