In February 2000, aged just 16 and still a schoolboy at Churchill School, Masakadza became the first black Zimbabwean to score a first-class century. He made his Test debut soon after, in July 2001, against the West Indies in Harare. In his team's second innings, he made 119, thus becoming - at the age of 17 years and 354 days - the youngest player to make a century on his Test debut. However, he only held this record for less than two months, before it was broken by Bangladesh's Mohammad Ashraful.
After briefly putting his professional cricket career on hold to study at the University of the Free State, Masakadza was recalled to the national team in late 2004 following the rebel crisis, and has maintained a regular presence since.
During the team's six-year exile from Test cricket (2005–2011), he increased his ability in One Day Internationals. His first century in this format came on 14 August 2009, against Bangladesh in Bulawayo, and in October 2009 he made scores of 156 and 178 not out in a home ODI series against Kenya - thus becoming the first Zimbabwean to make two scores of 150 or more in ODIs, and the first player from any country to make two such scores in the same series.
When Zimbabwe made its return to Test cricket in August 2011, playing a one-off match against Bangladesh in Harare, Masakadza made 104 in the first innings - thus making his second Test century ten years after his first. In 2015, he made his first appearance in the senior Cricket World Cup, having previously made two appearances in the Under-19 version (in 2000 and 2002).
As of November 2015, Masakadza is Zimbabwe's sixth-highest Test run-scorer and fifth-highest ODI run-scorer. He is also the country's leading Twenty20 International run-scorer, becoming the first Zimbabwean to reach 1,000 runs in this format on 29 September 2015.
In Zimbabwe's tour of Bangladesh in January 2016, Masakadza set a world record for the most runs scored in a T20I bilateral series, with a total of 222 across four games.
Following India's tour to Zimbabwe in June 2016, Masakadza became the first Zimbabwean cricketer to play in 50 Twenty20 International matches.