[2] Santa Cruz made his professional debut, at the age of 18 on 13 October 2006 against Mexican boxer Pedro Silva, winning the fight via knockout in round 2.
After drawing his second bout in January 2007 against Rodrigo Hernandez, Santa Cruz went on to win his next thirteen fights, with five coming by stoppage.
[3] In March 2011, Santa Cruz knocked out the veteran Stephane Jamoye to win the vacant WBC Youth bantamweight championship.
[4] In April 2012, promoter Branco Milenkovic announced that a deal was set for Santa Cruz to fight South African boxer Vusi Malinga (20–3–1, 12 KOs) for the vacant IBF bantamweight title.
[6][7][8] In August 2012, it was announced that Santa Cruz would make the first defence of his IBF title on the undercard of Saul Álvarez vs. Josesito López on 15 September at the MGM Grand Garden Arena in Paradise, Nevada.
[11][12] On 29 October 2012 a deal was reached for Santa Cruz to make a second defence of his IBF title at the Staples Center in Los Angeles against Mexican boxer Victor Zaleta (20–2–1, 10 KOs) on a double header featuring WBC super bantamweight champion Abner Mares vs. Anselmo Moreno on 10 November.
[13] Santa Cruz dropped Zaleta three times en route to a TKO victory in round 9 to retain his IBF title.
The last time CBS aired live boxing was 15 years prior in January 1997 when Bernard Hopkins stopped Glen Johnson.
Santa Cruz, who was known to have a high punch output did not throw as much as his previous bouts but did enough for the three judges to score the fight 116–112, 118–110, and 119–109 in his favour.
[21] Santa Cruz had his first fight at the super bantamweight limit on the undercard of the Floyd Mayweather Jr. vs. Robert Guerrero Showtime Pay-Per-View on 5 May 2013 at the MGM Grand in Las Vegas.
By the end of round 2, Terrazas' right eye began to close due to the offence output of Santa Cruz.
In round 3, Santa Cruz dropped Terrazas twice and although he beat the count each time, the referee waved off the fight after the second knockdown.
[31][32][Video 1] Golden Boy initially tried to make Santa Cruz vs. Cristian Mijares for 2 November however negotiations broke down on 9 October.
Instead a new deal was being formed for Santa Cruz to make his first voluntary defence against Cesar Seda (25–1, 17 KOs) on 14 December at the MGM Grand in Las Vegas, Nevada on the undercard of the Showtime PPV Marcos Maidana vs. Adrien Broner for the WBA welterweight title.
[35][36] CompuBox Stats showed that Santa Cruz landed 297 of 829 punches thrown (36%) and Seda landed 170 of his 649 thrown (26%)[37] On 9 January 2014 it was announced that Santa Cruz would finally meet veteran Mexican contender Cristian Mijares (49–7–2, 24 KOs), also his mandatory challenger at the MGM Grand Garden Arena in Paradise, Nevada on 8 March, defending his WBC title.
[42] Santa Cruz made his next defence on 13 September at the MGM Grand on the Mayweather-Maidana II undercard against Mexican boxer Manuel Roman (17–2–3, 6 KOs) .
"[45] Three months later on 17 January 2015 Santa Cruz defended his WBC super bantamweight title against Jesus Ruiz (33–5–5, 22 KOs) at the MGM Grand Garden Arena.
His opponent was announced as Mexican Jose Cayetano (17–3, 8 KOs) in a scheduled 10 round bout on the Mayweather vs. Pacquiao super fight undercard at the MGM Grand Arena.
[59] In January 2016, Showtime announced they would televise Santa Cruz's first defence against Kiko Martínez (35–6, 26 KOs), scheduled to take place on 28 February at the Honda Center in Anaheim, California.
Martínez was knocked down twice in Round 1, but beat the referee's count and continued to back Santa Cruz up in an entertaining slugfest.
Santa Cruz continued with a series of combinations until referee Raul Caiz Sr. jumped in at 2:09 as Martínez stopped throwing back.
[65] In a potential fight of the year candidate, Santa Cruz lost his title to Frampton via a 12-round majority decision win before a crowd of 9,062.
Originally discussed to take place at Frampton's hometown of Belfast, the venue was confirmed to be at the MGM Grand in Las Vegas on 28 January 2017.
[74] On 3 April 2017 the World Boxing Association ordered a rematch between Santa Cruz and their "regular" champion Abner Mares (30–2–1, 15 KOs).
Mares became mandatory challenger and "regular" titleholder after winning a split decision against Argentine boxer Jesus Cuellar in December 2016.
The fight would take place in the afternoon, on the same card Jermell Charlo defends his WBC light middleweight title against Erickson Lubin in the evening on Showtime.
The end came with Santa Cruz piling hurtful power shots on Avalos, when referee Thomas Taylor had seen enough, he stepped in at 1 minute, 34 seconds.
The three judges Rey Danseco of the Philippines, Steve Weisfeld, and Zac Young both of the United States scored the fight 115–113, 116–112 and 117–111, respectively, in favor of Santa Cruz.
[101] In his post-fight interview, Santa Cruz called out Gary Russell and stated that he'd be willing to move up to lightweight for a potential fight with Gervonta Davis.
[102] In April 2020, it was confirmed by Mayweather Promotions that Santa Cruz would be Gervonta Davis’ next opponent, although a June fight date was postponed due to the ongoing COVID-19 pandemic.