Hailing from Melbourne, Victoria, Handscomb was born to British parents. In his childhood days, he excelled in Tennis but he decided to pursue a career in cricket. He is a versatile middle-order batter and is assured both against pace and spin. Debuting for Victoria in 2011-12, he made a good impression with a knock of 71 runs against Queensland at the Gabba. He also scored a brilliant 113 at the Adelaide Oval in the domestic circuit in 2012. At that time, Matthew Wade had got injured and so, Handscomb was given the responsibility to do wicket-keeping for his side. That landed him a contract with the Melbourne Stars in the Big Bash League. The talented young man has played county cricket for Gloucestershire in 2015 as well. In 2016, he got a taste of the Indian T20 league as he was picked up by Pune in the auctions.

Handscomb was selected in the Australian ODI squad that was touring England in 2015 but didn't play a match. Consistently churning up runs for Victoria for a period of time didn't go unnoticed and he was rewarded with a Test call-up in 2016-17. He made his debut against South Africa at Adelaide Oval in the third game of the series. A debut to remember, Handscomb stroked himself to a well-constructed fifty. He also scored the winning run for his country, something that he will always cherish.

After that, Pakistan were touring Australia in December 2016 and Handscomb notched up his form one step further. He scored a ton in his second Test match and scored another one later in the series, kicking off 2017 in style. When the Australian summer came to an end, Handscomb achieved a commendable record. In his first seven innings of Test cricket, he never departed below 50 and became the first player in Test history to do so. The team from Down Under then travelled to India in February 2017. An unbeaten 72 from Handscomb in the third Test in Ranchi was a testament to his potential. He combined with Shaun Marsh and kept the Indians at bay for a long time, thereby saving the match for his side. Handscomb proved his skills later in 2017 in Bangladesh as well. He scored a gutsy 82 in Chittagong in tricky conditions.

Though dropped during the 2017–18 Ashes series, he remained prominent in white-ball plans, producing his signature ODI innings in March 2019 when he hit a match-winning 117 off 92 balls against India in Mohali to help chase down 359. He subsequently featured in Australia's 2019 Cricket World Cup squad, playing in the semi-final against England.

Despite losing his central contract for periods, Handscomb remained a prolific run-scorer in domestic cricket. As captain of Victoria, he dominated the Sheffield Shield, crossing 7,000 first-class runs for his state. His consistency extended to English county cricket, where he captained Middlesex before transitioning to Leicestershire in 2023. Highlights of his English stint included scoring a hundred at Lord's against his former side in 2024 and delivering consecutive 1,000-run county seasons.

Handscomb’s mastery of spin earned him a red-ball recall for Australia’s 2023 Test tour of India, where he played all four Border-Gavaskar Trophy matches. His crucial unbeaten 72 in Delhi proved instrumental in combating difficult subcontinental conditions.

In domestic cricket, Handscomb continues to be Victoria’s batting bedrock, transitioning into a mentor role alongside new captain Will Sutherland. His 2025–26 Shield campaign was a standout, yielding 724 runs with two centuries to lead Victoria to the final and earn him the captaincy of Cricket Australia's Sheffield Shield Team of the Season. His form kept him in national contention, earning selection as a senior leader in the Australia A squad for the four-day tour of India in September 2026.