Dispatchers received several calls late Sunday reporting an explosion, with one neighbour saying his whole house shook.
Firefighters found the house engulfed in flames, the front windows blown out and the front wall pushed out several centimetres.
Crews were able to get the flames under control in less than 20 minutes.
Craig Young, Saskatoon Fire and Protective Services battalion chief, says two people inside were able to escape the blaze, but were badly burned.
A 31-year-old man suffered second-degree burns and was in stable condition, while a 23-year-old man sustained second- and third- degree burns and was in serious condition.
"They're pretty lucky to get out. I have no idea exactly how they got out," Young said. "I was told that they had to dive out a window ... they were keeping pretty quiet as to what happened."
Investigators are still working to determine the exact cause.
Saskatoon police spokeswoman Alyson Edwards said there is no evidence the explosion is linked to a drug lab.
"I know that there is some speculation around that," she said. "There is no evidence at all that there was any meth lab or grow-op."
Damage is estimated at about $100,000.