But, after two other short times with Lucchese and Crotone, Papadopulo finally had his luckiest success for A.C. Siena (2001–2004), leading the team from Serie C1 to its first Series A ever, and even maintaining the top division the next year. Papadopulo was nicknamed il Papa (The Pope) by Siena fans during his period in the team, that he led from Series C to the Italian top division.
During the 2004–2005 season, Papadopulo was appointed as new coach of Lazio, replacing Domenico Caso; however, he left his managing position at the end of the season. On 29 January 2006, Papadopulo has been called back to Sicily in order to replace Luigi Delneri at the helm of U.S. Città di Palermo, and debuted with a surprising 3–0 win against AC Milan for a match of Italian Cup. After a series of impressive results which led Palermo off the lower places in the standings, and despite a one-year renewal signed before the end of the season, Papadopulo was dismissed from the rosanero, in order to be replaced by Francesco Guidolin.
On 28 December 2006 he became the new manager of Serie B club Lecce. In his second season with the giallorossi, Papadopulo obtained a third place in the Serie B final table, and then managed to defeat Pisa and AlbinoLeffe in the promotion playoffs, thus securing promotion to the top flight. Despite this, he left the club weeks later, after failing to reach an agreement with the club, who eventually decided to appoint Mario Beretta at his place.
On 20 October 2009 Papadopulo was fired as head coach of Bologna replaced by Franco Colomba.
On 9 March 2011 he was named new head coach of Serie B fallen giants Torino in place of Franco Lerda. His tenure at the helm of Torino turned out to last only a bare eleven days, marked with two defeats that convinced club chairman Urbano Cairo to remove Papadopulo from his managerial duties on 20 March and reinstate Lerda at the head coaching position.