Born in Burnside, Iowa, Mollenhoff graduated from high school in Webster City, Iowa. He began working for the Des Moines Register in 1942 while attending Drake University law school, from which he graduated in 1944. Mollenhoff then served two years in the Navy before returning to the Register.

In 1958 Mollenhoff won the Pulitzer Prize for National Reporting, for a series exposing racketeering and fraud in the Teamsters Union. His work led to a successful crack-down on the corruption.

In 1959 he received the Elijah Parish Lovejoy Award as well as an honorary Doctor of Laws degree from Colby College.

In 1969 he served for a year as Special Counsel to President Richard Nixon, after which he became the Register's Washington bureau chief.

In 1977 Mollenhoff became a professor at Washington and Lee University in Lexington, Virginia while continuing to write a column for the Register.

In 1988 he wrote a biography of John Vincent Atanasoff, the Iowa State University professor who invented the first electronic digital computer in 1939. Mollenhoff's book reveals the facts behind the 1973 federal court decision of Honeywell v. Sperry Rand that ruled the ENIAC computer patent invalid, and increased attention to Atanasoff's work.

Mollenhoff wrote twelve books and won many additional awards. He died in 1991 at age 69.

The Clark Mollenhoff Award for Excellence in Investigative Reporting is awarded annually by the Institute on Political Journalism for the best investigative journalism article in a newspaper or magazine.