Wylie Post was born in Grand Saline, Texas (Van Zandt County), to cotton farmer parents William Francis and Mae Quinlan Post. His family moved to Oklahoma when he was five. He was an indifferent student, but managed to complete the seventh grade. By 1920, his family settled on a farm near Maysville, Oklahoma.

Young Wiley's first view of an aircraft in flight came in 1913 at the county fair in Lawton, Oklahoma. The plane was a Curtiss-Wright "Pusher type." The event so inspired him that he immediately enrolled in the Sweeney Automobile and Aviation School in Kansas City. Seven months later, he returned to Oklahoma and went to work at the Chickasaw and Lawton Construction Company.

During World War I, Post wanted to become a pilot in the U.S. Army Air Service (USAS). Joining the training camp at the University of Oklahoma, he learned radio technology. Germany surrendered before he completed his training, the war ended, and he went to work as a "roughneck" in the Oklahoma oilfields. The work was unsteady and he turned briefly to car jacking. He was arrested in 1921 and sent to the Oklahoma State Reformatory where he served 14 months of a ten-year sentence, before being paroled.

Post's aviation career began at age 26 as a parachutist for a flying circus, Burrell Tibbs and His Texas Topnotch Fliers, and he became well known on the barnstorming circuit. On October 1, 1926, an oil field accident cost him his left eye, but he used the settlement money to buy his first aircraft. Around this time, he met fellow Oklahoman Will Rogers when he flew Rogers to a rodeo, and the two eventually became close friends. Post was the personal pilot of wealthy Oklahoma oilmen Powell Briscoe and F.C. Hall in 1930 when Hall bought a high-wing, single-engine Lockheed Vega, one of the most famous record-breaking aircraft of the early 1930s. The oilman nicknamed it the Winnie Mae after his daughter, and Post achieved his first national prominence in it by winning the National Air Race Derby, from Los Angeles to Chicago. The fuselage was inscribed, "Los Angeles to Chicago 9 hrs. 8 min. 2 sec. August 27, 1930." Adam Charles Williams finished second with a time of 9 hrs. 9 min. 4 sec.

In 1930 the record for Flying around the world was not held by a fixed-wing aircraft, but by the Graf Zeppelin, piloted by Hugo Eckener in 1929 with a time of 21 days. On June 23, 1931, Post and his navigator, Harold Gatty, left Roosevelt Field on Long Island, New York in the Winnie Mae with a flight plan that would take them around the world, stopping at Harbour Grace, Flintshire, Hanover twice, Berlin, Moscow, Novosibirsk, Irkutsk, Blagoveshchensk, Khabarovsk, Nome where his propeller had to be repaired, Fairbanks where the propeller was replaced, Edmonton, and Cleveland before returning to Roosevelt Field. They arrived back on July 1, after traveling 15,474 miles (24,903 km) in the record time of 8 days and 15 hours and 51 minutes. The reception they received rivaled Charles Lindbergh's everywhere they went. They had lunch at the White House on July 6, rode in a ticker-tape parade the next day in New York City, and were honored at a banquet given by the Aeronautical Chamber of Commerce of America at the Hotel Astor. After the flight, Post acquired the Winnie Mae from F.C. Hall, and he and Gatty published an account of their journey titled, Around the World in Eight Days, with an introduction by Will Rogers.

After the record-setting flight, Post wanted to open his own aeronautical school, but could not raise enough financial support because of doubts many had about his rural background and limited formal education. Motivated by his detractors, Post decided to attempt a solo flight around the world and to break his previous speed record. Over the next year, Post improved his aircraft by installing an autopilot device and a radio direction finder that were in their final stages of development by the Sperry Gyroscope Company and the United States Army. In 1933, he repeated his flight around the world, this time using the auto-pilot and compass in place of his navigator and becoming the first to accomplish the feat alone. He departed from Floyd Bennett Field and continued on to Berlin where repairs were attempted to his autopilot, stopped at Königsberg to replace some forgotten maps, Moscow for more repairs to his autopilot, Novosibirsk, Irkutsk for final repairs to the autopilot, Rukhlovo, Khabarovsk, Flat where his propeller had to be replaced, Fairbanks, Edmonton, and back to Floyd Bennett Field. Fifty thousand people greeted him on his return on July 22 after 7 days, 18 hours, 49 minutes - 21 hours less than his previous record, and he was given a second ticker-tape parade in New York.

In 1934, with financial support from Frank Phillips of the Phillips Petroleum Company, Post began exploring the limits of high-altitude long-distance flight. The Winnie Mae's cabin could not be pressurized, so he worked with Russell S. Colley of the B.F. Goodrich Company to develop what became the world's first practical pressure suit. Three pressure suits were fabricated for Wiley Post; only the final version proved successful. The first suit ruptured during a pressure test. The redesigned second suit used the same helmet as the first but when tested was too tight and they were unable to remove it from Post, so they had to cut him out thus destroying the suit. The third suit was redesigned from the previous two.
 
The body of the suit had three layers: long underwear, an inner black rubber air pressure bladder, and an outer layer made of rubberized parachute fabric. The outer layer was glued to a frame with arm and leg joints that allowed him to operate the flight controls and to walk to and from the aircraft. Attached to the frame were pigskin gloves, rubber boots, and an aluminum-and-plastic diver's helmet. The helmet had a removable faceplate that could be sealed at a height of 17,000 ft, and could accommodate earphones and a throat microphone. The helmet was cylinder-shaped with a circular window. In the first flight using the suit on September 5, 1934, Post reached an altitude of 40,000 ft. above Chicago. Eventually flying as high as 50,000 ft, Post discovered the jet stream and made the first major practical advances in pressurized flight.