Mpofu made his first-class debut for Matabeleland against Manicaland in March 2004, taking three wickets on debut. In the 2004/05 Faithwear Inter-Clothing Provincial One-Day Competition, Mpofu was the leading wicket-taker with 11 wickets. He repeated the performance with again in the 2005/06 edition with 9 wickets.

Following the mass exodus of top level players in the Zimbabwean cricket crisis of 2004, Mpofu made his One-Day International debut against England, and cost the English team some anxious moments.

Following the exodus of the rebels, Mpofu was given his Test debut against Bangladesh at the M. A. Aziz Stadium, Chittagong. He had scores of 0 and 5 in the match. The match was an indication of Zimbabwe's horrific decline in Tests as Bangladesh secured their maiden Test victory that too by a major 226 runs.

One definite shortcoming, is his crease occupation. Not content with being stumped twice in an afternoon (for a pair) in the first Test against New Zealand in August 2005, he followed up by being run out for 3 in the second match, as he strolled down the pitch to congratulate his teammate Blessing Mahwire on reaching his half-century, with the ball still in action. He still tends to blow hot and cold and has few rivals in the race to be considered international cricket's worst batsman.

Despite containing the basics, a good away movement, and a good action, Mpofu struggled, as for a long time he was the lone seamer among a cluster of spinners, and he had no one to help him out, and consistency was a major problem for the young seamer. There was a game against Pakistan in which he took 1/75.

International comeback

As Mpofu later recalled, Zimbabwe's short tour of South Africa in 2010 was the most toughest part of his life. On flat batting pitches without any assistance to seamers, Mpofu recorded unflattering bowling figures of 1 for 59 in the Twenty20 match in Kimberley, and 0/59 in a One-Day International at Bloemfontein. Mpofu later said that he thought about Mick Lewis in that 438-game and how he never played for Australia again, and whether the same fate would befall Mpofu too.^[11]

It was former Zimbabwean fast-bowling great Heath Streak who helped Mpofu believe he could. When Streak was appointed as bowling coach, Mpofu had a sense that things were changing. The two had a more good understanding because Streak who also came from Matabeleland as Mpofu spoke in his mother language, Ndebele. Streak told Mpofu that in cricket, he needed a wider repoirtoire of balls. Furthermore, former English Test cricketer Robin Jackman told him after his disastrous performances in South Africa that if he had to succeed in international cricket, he will have to bowl a slower ball. Mpofu first tried that experiment in the nets, and following success there, tried them in an international match situation. This chain of incidents proved to be a turning point in Mpofu's career.^[12]

A string of decent performances followed in the 2010 tri-series against India and Sri Lanka, as Zimbabwe beat India (twice) and Sri Lanka (once) to reach the final ahead of favorites India, ultimately finishing as runners-up. Mpofu continued in the same vein in the team's tour of Ireland. Mpofu took 8 wickets from this two combined series.^[13]

2011 Cricket World Cup

Mpofu had a fine World Cup 2011 performance, with 7 wickets at an average of 22.71 from 4 matches and eased into a more senior