Di Francesco started his career with Tuscan teams Empoli and Lucchese. In 1995 he joined Piacenza, where he had the opportunity to play regularly in the top flight. In 1997 he was signed by AS Roma, winning an Italian championship title in 2001 with the giallorossi and also making a few appearances for the Italian national team. Following this triumph, he agreed to return to Piacenza, for 2 billion Italian lire and then retired in 2005 following stints with Ancona and Perugia.
He then served as head coach of Pescara in the 2010–11 Serie B, guiding his team to an impressive season also thanks to glimpses of attractive football. On June 2011 it was revealed Di Francesco had left Pescara by mutual consent in order to hold talks with Serie A club Lecce regarding the vacant head coaching post at the club from Salento. He was removed from his managerial duties on 4 December 2011, after achieving only eight points in thirteen games, and leaving his side at the bottom of the league table.