First IBF flyweight title reign

On 5 July 2009, Mthalane's promoter Branco Milenkovic revealed that Mthalane was designated by the IBF as the mandatory challenger for Nonito Donaire IBF flyweight title. Before the terms of the fight could be negotiated however, Donaire vacated the title and moved up to super flyweight. Accordingly, the IBF ordered a fight between Eric Ortiz and Julio Cesar Miranda to determine who would fight Mthalane for the vacant title,^[2] with Miranda winning by a first-round knockout. The fight for the vacant world title was scheduled for 20 November 2009, and was held at the Wembley Indoor Arena in Johannesburg, South Africa.^[3] Mthalane won the fight by unanimous decision, with scores of 117-111, 117-111 and 118-111. He became the third South African fighter in 2009 to win a major IBF title.^[4]

On 1 March 2010, Zolani Tete was designated as the IBF flyweight mandatory title challenger after defeating Richard Garcia by unanimous decision in an IBF flyweight title eliminator.^[5] The IBF flyweight world title fight between Mthalane and Tete was scheduled for 1 September 2010, at the Carnival City in Brakpan, South Africa. Mthalane won the fight by knockout, stopping Tete at the 2:27 minute mark of the fifth round.^[6]

Mthalane made his second IBF title defense against Johnriel Casimero on 26 March 2011 at the Nasrec Indoor Arena in Johannesburg, South Africa. Mthalane won the fight by a fifth-round technical knockout. The bout was high in both pace and volume from the beginning, with Casimero fading as the fight went on, before he stopped defending himself effectively in the fifth round.^[7]

Mthalane was scheduled to make his third title defense against Andrea Sarritzu on 28 October 2011. The bout took place at the PalaRockfeller in Cagliari, Italy, which was his first fight outside of the South African Republic. Mthalane stopped the 35-year-old Sardinian by a seventh-round technical knockout, after Sarritzu's corner threw in the towel.^[8]

On 1 June 2012, the IBF ordered Mthalane to defend his title against Ricardo Nunez, giving the two camps a 30-day negotiation period to come to terms.^[9] Mthalane had a great start to the fight, as he managed to knock Nunez down in the second minute of the first round. Nunez knocked Mthalane down in turn in the third round, and began to take over the fight from that point until the seventh round. Mthalane rallied back in the from that point forward, before finally stopping Nunez in the eight round.^[10]

Mthalane was stripped of the IBF title in January 2014, after failing to come to terms with mandatory challenger Amnat Ruenroeng.^[11]

IBO flyweight champion

Second IBF flyweight title reign

It was announced on 17 October 2017, that the #10 ranked IBF flyweight contender Mthalane would face Ardin Diale for the vacant IBF International flyweight title.^[22] Mthalane won the fight by a second-round technical knockout. Following this victory, his promoter Tshele Kometsi began negotiating with the IBF for an IBF title eliminator bout.^[23]