Winfrey was born into poverty in rural Mississippi to a teenage single mother and later raised in an inner-city Milwaukee neighborhood. She experienced considerable hardship during her childhood, including being raped at the age of nine and becoming pregnant at 14; her son died in infancy. Sent to live with the man she calls her father, a barber in Tennessee, Winfrey landed a job in radio while still in high school and began co-anchoring the local evening news at the age of 19. Her emotional ad-lib delivery eventually got her transferred to the daytime talk show arena, and after boosting a third-rated local Chicago talk show to first place she launched her own production company and became internationally syndicated.

Credited with creating a more intimate confessional form of media communication, she is thought to have popularized and revolutionized the tabloid talk show genre pioneered by Phil Donahue, which a Yale study claims broke 20th century taboos and allowed LGBT people to enter the mainstream. By the mid 1990s she had reinvented her show with a focus on literature, self-improvement, and spirituality. Though criticized for unleashing confession culture and promoting controversial self-help fads, she is generally admired and has been praised for overcoming adversity to become a benefactor to others. In 2006 she became an early supporter of Barack Obama and one analysis estimates she delivered over a million votes in the close 2008 Democratic primary race, an achievement for which the governor of Illinois considered offering her a seat in the U.S. senate.

Though there are conflicting reports as to how her name became "Oprah", Winfrey was originally named "Orpah" after the Biblical character in the Book of Ruth. Her family and friends' inability to pronounce "Orpah" caused them to put the "P" before the "R" in every place else other than the birth certificate.

Winfrey was born in Kosciusko, Mississippi to unmarried parents. She later explained that her conception was due to a single sexual encounter that her two teenage parents had; they broke up not long after. Her mother, Vernita Lee, was a housemaid. Growing up, Winfrey believed that her biological father was Vernon Winfrey, a coal miner turned barber turned city councilman who was in the Armed Forces when she was born. Decades later, Mississippi farmer and World War II veteran Noah Robinson Sr. claimed to be her biological father.

After her birth, Winfrey's mother traveled north and Winfrey spent her first six years living in rural poverty with her grandmother, Hattie Mae Lee, who was so poor that Winfrey often wore dresses made of potato sacks, for which the local children made fun of her. Her grandmother taught her to read before the age of three and took her to the local church, where she was nicknamed "The Preacher" for her ability to recite Bible verses. When Winfrey was a child, her grandmother would take a switch and would hit her with it when she didn't do chores or if she misbehaved in any way.

At age six, Winfrey moved to an inner-city neighborhood in Milwaukee, Wisconsin with her mother, who was less supportive and encouraging than her grandmother had been, due in large part to the long hours Vernita Lee worked as a maid. Winfrey has stated that she was molested by her cousin, her uncle, and a family friend, starting when she was nine years old, something she first revealed to her viewers on a 1986 episode of her TV show, when sexual abuse was being discussed.

At 13, after suffering years of abuse, Winfrey ran away from home. When she was 14, she became pregnant, but her son died shortly after birth. Also at that age, her frustrated mother sent her to live with Vernon in Nashville, Tennessee. Vernon was strict, but encouraging and made her education a priority. Winfrey became an honors student, was voted Most Popular Girl, joined her high school speech team at East Nashville High School, and placed second in the nation in dramatic interpretation. She won an oratory contest, which secured her a full scholarship to Tennessee State University, a historically black institution, where she studied communication. Her first job as a teenager was working at a local grocery store. At age 17, Winfrey won the Miss Black Tennessee beauty pageant. She also attracted the attention of the local black radio station, WVOL, which hired her to do the news part-time. She worked there during her senior year of high school, and again while in her first two years of college.

Winfrey's career choice in media did not surprise her grandmother, who once said that ever since Winfrey could talk, she was on stage. As a child she played games interviewing her corncob doll and the crows on the fence of her family's property. Winfrey later acknowledged her grandmother's influence, saying it was Hattie Mae who had encouraged her to speak in public and "gave me a positive sense of myself."

Working in local media, she was both the youngest news anchor and the first black female news anchor at Nashville's WLAC-TV. She moved to Baltimore's WJZ-TV in 1976 to co-anchor the six o'clock news. She was then recruited to join Richard Sher as co-host of WJZ's local talk show People Are Talking, which premiered on August 14, 1978. She also hosted the local version of Dialing for Dollars there as well.

In 1983, Winfrey relocated to Chicago to host WLS-TV's low-rated half-hour morning talk show, AM Chicago. The first episode aired on January 2, 1984. Within months after Winfrey took over, the show went from last place in the ratings to overtaking Donahue as the highest rated talk show in Chicago. It was renamed The Oprah Winfrey Show, expanded to a full hour, and broadcast nationally beginning September 8, 1986. On her 20th anniversary show, Oprah revealed that movie critic Roger Ebert was the one who persuaded her to sign a syndication deal with King World. Ebert predicted that she would generate 40 times as much revenue as his television show, At the Movies. Already having surpassed Donahue in the local market, Winfrey's syndicated show quickly doubled Donahue's national audience, displacing Donahue as the number one day-time talk show in America. Their much publicized contest was the subject of enormous scrutiny.