Cheptegei, also the world record holder, led for large periods of the race and held off all challengers on the final lap at Eugene's Hawyard Field to clock a winning time of 27min 27.43sec.
Kenya's Stanley Waithaka Mburu claimed silver in 27:27.90, with another Ugandan, Jacob Kiplimo, taking bronze (27:27.97) in an unsually close finish.
"I did not aim to run really fast because of the heat, the sun was very strong," Cheptegei said. "The conditions were kind of challenging.
"You just have to enjoy the race and see how it is going. Then it was going good."
Cheptegei added: "I knew that if I get into the last fight, I can control it and I could speed it up. I was able to get stronger and keep it faster and faster."
Spain's Carlo Mayo took up the early running, the loaded field quickly splitting into single file.
Uganda's Stephen Kissa and Cheptegei then moved to the front at the 3km mark, reigning Olympic champion Selemon Barega briefly surging through the 5km mark in 14.01.
Kiplimo put in a shift up front, further splitting the pack to a lead group of 15, perhaps bigger than the east Africans might have liked.
Heading into the final two laps, Barega and Mburu shot to the front, setting up a grandstand finish as a pack of eight went through the bell for the final 400 metres.
Long-time leader Cheptegei was in no doubt about what his race plan was, kicking past the pair at 300 metres and easily holding off all-comers down the back stretch, around the final bend and towards the home straight in a consummate display of distance running.
Ethiopia's Barega finished fifth, beaten to fourth by American Grant Fisher.
It was not the result Barega wanted and he didn't hold back.
"I did not only expect to get a medal in Eugene but I was targeting the gold," he said.
"So you can see that the disappointment is very big. I did not control the race, did not watch the other runners and was trying to run my own pace. Maybe that was a big mistake in the end.
"This definitely was a big lesson for me and I will try to not to repeat it in the future. I still plan to run 5000m here so I hope to bring some better result for my country."