A wagon train heads west from Independence, Mo., along the Oregon Trail, led by proud cowboy Clint Belmet. On board are feisty young widow Nancy Wellington and her toddler, Sonny, as well as the older Abby Masters, who begins a romance with scout Jim Burch. Along the way, the wagon train battles Indians led by Kenneth Murdock, a trapper who doesn't welcome competition for Oregon's lucrative fur trade. Wagon Wheels is a 1934 remake of 1931's Fighting Caravans, using stock footage from the original.

"Nevada" and "Weary" Pierce hijack the loot taken in a bank hold-up by Les Setter, and his gang. They escape from Sheriff Jim Henry Warner. U. S. government horse-buyer David Ward is killed by Settler's men and Settler takes his papers and goes to the ranch of Blaine and asks for the horses Ward was to buy, promising payment from the government later. He also takes an interest in Ina Blaine, much to the resentment of her sweetheart Ben Ide. "Nevada" and "Weary" are hired for the horse round-up but Setter has them and Ben arrested on a fake charge.

Dare Rudd takes a shine to his cattleman cousin Tom's girlfriend who asks Tom to hire Dare to head the big cattle drive. Dare loses the money for the drive to cardsharps, but Tom wins it back, but Dare must save Tom's life.

A mining engineer teams up with a crusty deputy sheriff to solve the mystery killings at an old mine where the owner's family waits for him to die, and where a valuable radium strike may have been made.