Clyde Chestnut Barrow was born in 1909 into a poor farming family in the town of Telico in Ellis County, Texas. He was the fifth of seven children of Henry Basil Barrow (1874-1957) and Cumie Talitha Walker (1874-1942). The family moved to Dallas in the early 1920s as part of a wider migration pattern from rural areas to the city, where many settled in the urban slum of West Dallas. The Barrows spent their first months in West Dallas living under their wagon until they got enough money to buy a tent.

Barrow was first arrested in late 1926, at age 17, after running when police confronted him over a rental car that he had failed to return on time. His second arrest was with his brother Buck Barrow soon after, for possession of stolen turkeys. Barrow had some legitimate jobs from 1927 through 1929, but he also cracked safes, robbed stores, and stole cars. He met 19-year-old Parker through a mutual friend in January 1930, and they spent much time together during the following weeks. Their romance was interrupted when Barrow was arrested by Dallas County Sheriff's Deputy Bert Whisnand and convicted of auto theft. He escaped from the McLennan County Jail in Waco, TX, on March 11, 1930, using a gun Parker smuggled into the jail.

Recaptured on March 18, Barrow was sent to Huntsville State Prison in April 1930 and in September he was assigned to the Eastham Prison Farm at the age of 21. He was sexually assaulted while in prison, and he retaliated by attacking and killing his tormentor with a pipe, crushing his skull. This was his first murder. Another inmate who was already serving a life sentence claimed responsibility.

To avoid hard labor in the fields, Barrow purposely had two of his toes amputated in late January 1932, either by another inmate or by himself. Because of this, he walked with a limp for the rest of his life. However, without his knowledge, Barrow's mother had already successfully petitioned for his release and he was set free six days after his intentional injury. He was paroled from Eastham on February 2, 1932, now a hardened and bitter criminal. His sister Marie said, "Something awful sure must have happened to him in prison because he wasn't the same person when he got out." Fellow inmate Ralph Fults said that he watched Clyde "change from a school boy to a rattlesnake".

In his post-Eastham career, Barrow robbed grocery stores and gas stations at a rate far outpacing the ten or so bank robberies attributed to him and the Barrow Gang. His favorite weapon was the M1918 Browning automatic rifle (BAR). According to John Neal Phillips, Barrow's goal in life was not to gain fame or fortune from robbing banks but to seek revenge against the Texas prison system for the abuses that he had sustained while serving time. The injury slowed him down physically, making it harder to outrun law enforcement and limiting his mobility during his many robberies.