Manning was born in Kansas City, Missouri, but he came to live in Phoenix, Arizona. Manning's only art training occurred during high school. After graduating, Manning worked as a freelancer. In 1926, The Arizona Republic hired Manning as a photographer and artist. At first, Manning's work appeared in several forms in the paper. Although he was interested in drawing comic strips, the popularity of his editorial work led him to focus on editorial cartoons. His work was syndicated in as many as 170 newspapers.
Manning often used a small anthropomorphic cactus with a big nose as a visual signature. From 1948 until 1971, his work was syndicated by the McNaught Syndicate. In 1951, Manning won a Pulitzer Prize for Editorial Cartooning for an editorial cartoon entitled "Hats", which was a commentary on the Korean War.
Several of his books deal with Arizona and its cacti in particular, such as What Kinda Cactus Izzat? (also known as The Cactus Book), and What is Arizona Really Like?: A Guide to Arizona's Marvels.
Reg Manning did exceptional copper wheel engravings on crystal glass. See his book Desert in Crystal (1973). He also produced postcards, jewelry, stationery and water colors, all dealing with Western themes.
- Reg Manning's Cartoon Guide of Arizona, J. J. Augustine, 1938
- Reg Manning's Cartoon Guide of California, J. J. Augustine, 1939
- Reg Manning's cartoon guide of the Boulder dam country, J. J. Augustine, 1939
- What Kinda Cactus Izzat?, J. J. Augustine, 1941
- Little Itchy Itchy And Other Cartoons, J. J. Augustine, 1944
- From Tee to Cup, Reganson Cartoon Books, 1954
- What Is Arizona Really Like?, Reganson Cartoon Books, 1968
- Desert in Crystal, Reganson Cartoon Books, 1973
- Best of Reg, Reg Manning and Dean Smith, Arizona Republic, 1980
- "Reg Manning, 80, 'Cactus Cartoonist' - Los Angeles Times". Articles.latimes.com. 1986-03-16. Retrieved 2010-09-18.
- "Reg Manning Papers". Syracuse University. Retrieved 2010-11-09.
- "Social Security Death Index". Retrieved 2010-11-09.
- "Manning, Reg, 1905-1986". Library of Congress Authorities. Retrieved February 1, 2019.
- "The Cartoon Collection Of Reg Manning". Specialcollections.wichita.edu. Retrieved 2010-09-18.
- "ASU Libraries: On the Campaign Trail - Reg Manning Political Cartoons". Asu.edu. Retrieved 2010-09-18.