The blaze at the Hiroshima prefecture city's Hotel Prince broke out about 7 a.m. and was extinguished shortly after 10 a.m., Kyodo News reported.
The news agency said four women and two men were killed. The three people injured included an employee of the four-story hotel.
The condition of the injured and the cause of the blaze were not known.
There were about 20 people staying at the hotel at the time of the fire.