Di Michele, whose mother is from Casarano, began his career with Lodigiani in the Italian Serie C1 near to his hometown Guidonia Montecelio, and played for them from 1993 to 1996.

[3] Halfway through the 2005–06 season Di Michele's contract was sold to Palermo[4] for €5.35 million,[5] with Simone Pepe, Salvatore Masiello and Nicola Santoni moving to oppose direction in co-ownership deals.

In March 2007, Di Michele was found guilty of illegal betting and received a three-month ban from Serie A.

On 2 September 2008, Di Michele was loaned to West Ham United, with an option for the English club to make the deal permanent.

[15][16] After the incident the players involved: Di Michele, Massimo Loviso, Riccardo Colombo, Aimo Diana, Marco Pisano, Francesco Pratali, Paolo Zanetti were transferred to other clubs and only Rolando Bianchi, Matteo Rubin and Angelo Ogbonna were remained.

[18] In January 2013, Di Michele rescinded his contract with Chievo and was signed by his former club Reggina, eight years after leaving them.

He made his senior debut for Italy on 30 March 2005, at the age of 29, under coach Marcello Lippi, in a 0–0 friendly home draw against Iceland.

[20] He made his final appearance for Italy on 6 September 2006, under Roberto Donadoni, in a 3–1 away loss to France in a European qualifier.

[21] Di Michele retired in December 2015 to switch to a non-playing staff role at his latest club Lupa Roma.

In April 2016, he was named new joint head coach of the club, together with Angelo Quinzi, in place of Alessandro Cucciari.