[2][3] During his amateur career, Matthysse fought in the 2003 Pan American Games at Santo Domingo, Dominican Republic, where he went on to stop Colombia's Breidis Prescott in just the first round.
[6] On 6 November 2010 Matthysse lost a very disputed split decision against former world champion Zab Judah in the main event of an HBO card.
Judah continued to box throughout the ninth round but Matthysse began to show more power in the tenth, focusing on the head of his opponent and knocking down the American boxer after a hard right hand to the jaw.
[10] On 25 June 2011 Matthysse faced former world champion Devon Alexander and lost another close, but hugely controversial split decision.
Lucas was forced to withdraw from a fight versus Erik Morales in one of the featured bouts on the Floyd Mayweather Jr. vs. Victor Ortiz HBO PPV undercard at the MGM Grand in Paradise, Nevada, citing a viral infection that had kept him from training.
[14] Lucas fought Mexican Martín Ángel Martínez on 10 February 2012 for the vacant WBA Inter-Continental light welterweight title at the Gimnasio Municipal, Chubut, Argentina in a scheduled 12 round bout.
The stay-busy victory over the 20-year-old Mexican fighter set up a Showtime televised showdown between Matthysse and former 130-pound and lightweight beltholder Humberto Soto on 23 June 2012.
At the end of the second round Matthysse landed a hard right hand to the body followed of a left hook to the head, that knocked Peterson down.
He then faced unified 140 lb champion Danny García on 14 September 2013 as part of the undercard to the Floyd Mayweather vs. Saul Alvarez main event.
[17] Matthysse lost his WBA (Regular) welterweight title against Manny Pacquiao on 15 July 2018 at the Axiata Arena in Kuala Lumpur.