Commenting on Singleton's career, more than one of colleague of the MediaNews Group chairman referred to him as a "legend" in the business.
He was a part-time reporter in Graham, Texas, at age 15 and bought his first newspaper at age 21, The Denver Post reported Tuesday.
He founded MediaNews Group in 1983 with the late Richard Scudder. In time, it became the second largest newspaper business in the country, the Post said.
The company owns of the San Jose Mercury News, the St. Paul Pioneer Press, The Detroit News and The Salt Lake City Tribune, along with The Denver Post itself, which has won five Pulitzer Prizes since MediaNews Group bought it in 1987.
"Dean has been a fixture and important leader in Colorado for decades. He is impossible to replace," said Post editor Greg Moore.
"Working with a legend has been challenging and exhilarating," Moore said. "I'm going to miss him personally and professionally."
Singleton has battled with multiple sclerosis for 26 years and cited that as part of the reason he would step down.
"Fighting MS has actually caused me to be healthier in some aspects of my life. But it makes it more difficult to do the things you want to do," he said.
Singleton will remain involved at the Post, serving as a non-executive chairman, the newspaper reported. He will keep an office in Denver, but focus on helping his children run their businesses, the newspaper said.
Mac Tully, president and chief executive officer of the newspaper, will replace Singleton as publisher.
"Dean is a newspaper legend, and you don't replace a legend. Our job now will be to build on the great company Dean has created," said John Paton, chief executive officer of Digital First Media.