The shooting happened at the Payless Inn near 25th and Van Buren streets shortly before 11.30am local time, according to Phoenix police spokesman Sergeant Armando Carbajal.
Two adult males arrived at the hotel and got into an argument with a group on the second floor, Mr Carbajal said.
One of the men then pulled out a handgun and fired multiple shots, the officer said. The suspect is believed to be among the injured.
Those involved were were transported to the hospital, where the teenager was pronounced dead.
Three victims are in “extremely critical condition,” according to the police.
Mr Carbajal described the victims as three males and three females ranging from 18 to 41 years old.
Police are still searching for the other man who arrived with the shooter, according to police.
However, investigators do not believe he is a threat to the local community.
Police said streets in the area have been closed as they investigate the scene.