The legendary 'Pac Man' has not fought for more than two years since his decision win against Keith Thurman Jr.
Spence Jr was given the nod over bitter rival Terence Crawford to face Pacquiao in his comeback fight, and the 31-year-old will present a challenge for the Filipino senator like no other.
While all eyes will be on Pacquiao and Spence Jr, there are plenty of other intriguing bouts to keep boxing fans entertained until the main event.
The undercard also features at least two title fights, including the WBA 'Super' welterweight title and the WBC-ABC featherweight title.
Full Manny Pacquiao vs Errol Spence Jr undercard
Yordenis Ugas (26-4, 12 KOs) vs Fabian Maidana (18-1, 13 KOs) - WBA 'Super' welterweight title
Robert Guerrero (36-6-1, 20 KOs) vs Victor Ortiz (32-6-3, 25 KOs)
Mark Magsayo (22-0, 15 KOs) vs Julio Ceja (32-4-1, 28 KOs) - for WBC-ABC featherweight title
What time will Manny Pacquiao be fighting?
The main event ring walk is expected around 5am BST.
However, this is subject to change, due to the nature of the show.
What are the current odds?
Manny Pacquiao - 13/8
Draw - 18/1
Errol Spence Jr - 4/9
(Odds courtesy of Betfair)
The fight will be shown live on FOX SPORTS PPV with their broadcast starting at 2am BST.
A price has not yet been determined.News Now - Sport News