Brett Favre was born in Gulfport, Mississippi, the son of Bonita Ann (nee French) and Irvin Ernest Favre, and raised in the small town of Kiln. Both of his parents were schoolteachers in the Hancock County School District. He is of part French ancestry. One of his ancestors is Simon Favre, a Creole, was an influential figure in Spanish West Florida in the late 18th and early 19th centuries; Brett descends from Simon's Choctaw Native American mistress, Pistikiokonay, and thus his grandfather was affiliated with the Choctaw.

After high school, Southern Mississippi offered Favre a football scholarship, which was the only one he received. Southern Miss wanted him to play defensive back, but Favre wanted to play quarterback instead. Favre began his freshman year as the seventh-string quarterback and took over the starting position in the second half of the third game of the year against Tulane on September 19, 1987. Favre, despite suffering a hangover from the night before and vomiting during warm-ups, led the Golden Eagles to a come-from-behind victory with two touchdown passes. Favre started ten games during his freshman year and won six of them.  In his junior season, Favre led the Golden Eagles to an upset of #6 Florida State on September 2, 1989. Favre capped a six-and-a-half-minute drive with the game-winning touchdown pass with 23 seconds remaining.  On July 14, 1990, before the start of Favre's senior year at Southern Miss, he was involved in a near-fatal car accident. When going around a bend a few tenths of a mile from his parents' house, Favre lost control of his car, which flipped three times and came to rest against a tree. It was only after one of his brothers smashed a car window with a golf club that Favre could be evacuated and rushed to the hospital. In the ambulance, his mother was sitting with him. "All I kept asking [her] was 'Will I be able to play football again?'" Favre recalled later. Doctors would later remove 30 inches (76 cm) of Favre's small intestine. Six weeks after this incident, on September 8, Favre led Southern Miss to a comeback victory over Alabama. Alabama coach Gene Stallings said, "You can call it a miracle or a legend or whatever you want to. I just know that on that day, Brett Favre was larger than life."  Favre formerly held several Southern Miss football records until most were surpassed by Austin Davis by the end of the 2011 season. Favre had 15 games over his career where he compiled more than 200 passing yards, making him fourth in school history on the all-time list in that category. Of those 15 games, five were 300-yard games, the most compiled by any of the school's quarterbacks. Additionally, he was the seasonal leader in total passing and total offense in all four of his seasons at Southern Miss.

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