Swann has accepted an offer to fill one of the most challenging administration roles as the AFL's executive general manager football performance.
Swann, who has been involved in club administration for more than 25 years, will oversee hot issues including the match review system, umpiring and laws of the game.
Those flashpoint areas had previously fallen to executive general manager of football Laura Kane, who was demoted in an executive reshuffle last week.
AFL chief executive officer Andrew Dillon has split Kane's role, with the experienced Swann to depart Brisbane and start at the AFL on July 21.
"I'm leaving to go the AFL to head up footy, I suppose, in the simplest terms," Swann said when he confirmed his appointment to colleagues.
After his lengthy stints at three clubs, Swann added he is heading "to the mothership".
Kane will now be responsible for football operations for the AFL, AFLW, VFL and VFLW, among other duties, while Swann will take over the AFL's football performance.
Swann has held chief executive roles at Collingwood (from 2000), Carlton (from 2007) and the Lions since 2014.
"Greg, across his 26 years leading clubs, has earned a reputation as one of the most passionate and accomplished football CEOs in AFL, steering the on and off field turnaround of three of the competition's proudest clubs," Dillon said in a statement on Monday.
"Greg has a deep love and understanding of the game, he respects its heritage and has a great instinct on the future direction of footy.
"He understands how much it means for so many people."As I said last week, the game is the reason we exist; it is as big and as good as it has ever been, and the AFL football department must continue to evolve."
Later on Monday, the AFL confirmed that Brisbane chief operating officer Sam Graham would replace Swann as club CEO.