Knowles was first elected to the Wisconsin State Senate in 1940, becoming Majority Leader after only two years in office in 1943, but during World War II he took a break to serve as a lieutenant in the U.S. Navy aboard the USS Nevada.

[1] Following his military service, Knowles resumed serving in the Wisconsin State Senate and returned to the leadership position for 5 additional legislative terms until his election as lieutenant governor in 1954.

He placed fourth behind former Governor Walter J. Kohler Jr. and Congressmen Glenn R. Davis and Alvin O'Konski, receiving 8% of the vote.

[2] Elected governor narrowly over the Democratic incumbent John W. Reynolds in 1964 against the national Lyndon B. Johnson tidal wave, he served three two-year terms from 1965 to 1971.

After leaving the governor's chair, Knowles became chairman of Heritage Wisconsin Corporation, a Milwaukee bank holding company.

Knowles died after suffering a heart attack while participating in the Governor's Fishing Opener, an event he helped organize 25 years earlier.