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.
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.