Police and rescue teams were called to the scene of the accident on 50 Pi Rd at around 7pm.
Investigation officer Pol Lt Col. Chananarong Prakongkeo of the Patong Police responded, along with rescue workers from the Kusoldharm Phuket Foundation and forensic doctors from Vachira Phuket Hospital.
At the scene, officers found a red Honda Click motorbike, registered in Phuket, stopped near on the grass beside the road. Next to it lay the body of the American man, later identified as Larry Dean Chupp Jr, from georgia.
His 16-year-old niece, Isabella Marie Chupp, who had been riding pillion, was uninjured.
According to police, the pair had been returning from a meal on Bangla Rd to their accommodation when the incident occurred.
Mr Chupp reportedly complained of chest pain moments before losing control of the motorbike and veering off the road.
Officers said Mr Chupp had a known history of heart disease, and initial findings suggest a heart attack may have caused the incident. His family has not raised any suspicions regarding his death, police said.
The body was transported to Vachira Phuket Hospital for a post-mortem examination to confirm the cause of death. Officials have also notified the US Embassy to assist with consular procedures, police noted.