John Constantine Unitas was born in Pittsburgh in 1933 to Francis J. Unitas and Helen Superfisky, who both were of Lithuanian descent; he grew up in the Mount Washington neighborhood. When Johnny was five years old, his father died of cardiovascular renal disease complicated by pneumonia, leaving the young boy to be raised by his mother, who worked two jobs to support the family. His surname was a result of a phonetic transliteration of a common Lithuanian last name Jonaitis. Attending St. Justin's High School in Pittsburgh, Unitas played halfback and quarterback.

In 1956, Unitas joined the Baltimore Colts of the NFL under legendary coach Weeb Ewbank, after being asked at the last minute to join Bloomfield Rams lineman Jim Deglau, a Croatian steel worker with a life much like Unitas', at the latter's scheduled Colts tryout. The pair borrowed money from friends to pay for the gas to make the trip. Deglau later told a reporter after Unitas' death, "[His] uncle told him not to come. [He] was worried that if he came down and the Colts passed on him, it would look bad (to other NFL teams)." The Colts signed Unitas, much to the chagrin of the Cleveland Browns, who had hoped to claim the rejected Steeler quarterback. Unitas made his NFL debut with an inauspicious "mop-up" appearance against Detroit, going 0-2 with one interception. Two weeks later, starting quarterback George Shaw suffered a broken leg against the Chicago Bears. In his first serious action, Unitas' initial pass was intercepted and returned for a touchdown. Then he botched a hand-off on his next play, a fumble recovered by the Bears. Unitas rebounded quickly from that 58-27 loss, leading the Colts to an upset of Green Bay and their first win over Cleveland. He threw nine touchdown passes that year, including one in the season finale that started his record 47-game streak. His 55.6-percent completion mark was a rookie record. In 1957, his first season as the Colts full-time starter at quarterback, Unitas finished first in the NFL in passing yards (2,550) and touchdown passes (24) as he helped lead the Colts to a 7-5 record, the first winning record in franchise history. At season's end, Unitas received the Jim Thorpe Trophy as the NFL's Most Valuable Player by the Newspaper Enterprise Association (NEA).

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