Clower began a stint in the Navy immediately after graduating high school, then studied agriculture at Mississippi State University, where he played college football and was a member of Phi Kappa Tau Fraternity. After finishing school, Clower worked as a county agent and later as a seed salesman. He became a fertilizer salesman for Mississippi Chemical in 1954. By this time, he had developed a reputation for telling funny stories to boost his sales.

It was while speaking to the Alabama Dairy Convention in Point Cedar, Alabama in 1970 that an attendee enthusiastically told Clower he might have a future in comedy. Thinking there might be some potential in that area, Clower taped his next few speaking engagements. The "Coon Huntin' Story" that would launch his career was first taped in Corpus Christi, Texas at the state Farmer's Cooperative Convention. Eventually, Clower's tapes wound up in the hands of "Big Ed" Wilkes in Lubbock, Texas, who had Clower make a better quality recording and began promoting it.

At first, Clower was just taking orders at his speaking engagements. He sold 8000 copies this way on the Lemon record label. In time, Wilkes sent a copy to Grant Turner at WSM radio in Nashville, Tennessee, and when Turner played it on the air, Clower said "that thing busted loose." MCA was soon knocking on Clower's door offering him a contract. Once MCA began distribution in 1971, Jerry Clower from Yazoo City, Mississippi Talkin’ retailed more than a million dollars over ten months and stayed in the Top 20 on the country charts for 30 weeks.

Clower was 45 when MCA came calling and he began his professional career as a comedian. He often said, "I backed into show business." Many of his comedic stories revolved around the fictional Ledbetter family, especially his "best friend" Marcel Ledbetter. Those stories are considered to be informal chronicles of early 20th century rural Southern life and according to Clower, were usually based on actual events.

Clower recorded 27 full length recordings in his 27 year career as a professional entertainer (not counting "best of" compilations). With one exception, all the recordings were released by MCA. The exception was Ain't God Good which Clower recorded with MCA's blessing at a worship service. Word Records promoted and distributed this title in 1977. Always a staunch Christian, this recording gave Clower an opportunity to present his personal testimony in a comfortable church setting. The title of the recording was taken from a book Clower had written two years earlier (see below).

In 1973, Clower became a member of the Grand Ole Opry, and remained with that organization until his death. He also co-hosted a radio show called Country Crossroads with Bill Mack and Leroy Van Dyke for a number of years. This show was produced and distributed by the Southern Baptist Convention. Clower's last album was Peaches and Possums released in October 1998, after his death. He was the author of 4 books. The book Ain't God Good became the basis for an inspirational documentary film of the same title that won an award from the New York International Independent Film and Video Festival.

Clower died at age 71 after heart bypass surgery.