He made his List A debut on 20 April 2016 for Islamabad in the 2016 Pakistan Cup. On 26 August 2016, he made his Twenty20 debut for Rawalpindi in the 2016–17 National T20 Cup. After his impressive performance in the 2017 ICC Champions Trophy, he was signed to play for Trinbago Knight Riders in the 2017 Caribbean Premier League. Later in 2017, Khan signed with the Brisbane Heat for the 7th season of the Big Bash League.

In March 2017, he was named in Pakistan’s limited overs squad for their matches against the West Indies. He made his Twenty20 International (T20I) debut for Pakistan against the West Indies on 26 March 2017. He recorded the most economical figures for a bowler completing their four overs on debut in a T20I. The following month, he was added to Pakistan’s Test squad for their series against the West Indies.

He made his One Day International (ODI) debut for Pakistan against the West Indies on 7 April 2017. He made his Test debut for Pakistan, also against the West Indies, on 30 April 2017. He was part of Pakistan’s 2017 Champions Trophy winning squad. In September 2017, he was named as the PCB’s Emerging Player of the Year.

On 16 October 2017 against Sri Lanka, Shadab scored his maiden ODI fifty. Shadab, along with Babar Azam made a partnership of 109 and slowly built the innings towards 200. When bowling, Shadab took early breakthroughs in the low scoring game taking three wickets. Pakistan won the match by 32 runs and Shadab was adjudged man of the match for his all-round performances.

In June 2019, he was selected to play for the Edmonton Royals franchise team in the 2019 Global T20 Canada tournament.

In April 2019, he was named in Pakistan’s squad for the 2019 Cricket World Cup. Three days after Shadab was named in Pakistan’s World Cup squad, he was ruled out of Pakistan’s preceding tour of England with a virus. He was replaced by Yasir Shah for the matches against England. Ahead of the third ODI match against England, Pakistan’s captain, Sarfaraz Ahmed, confirmed that Shadab has recovered and would be fit enough to play at the World Cup. On 23 June 2019, in Pakistan’s World Cup match against South Africa, Shadab took his 50th wicket in ODIs.

In June 2020, he was named in a 29-man squad for Pakistan’s tour to England during the COVID-19 pandemic. However, on 22 June 2020, Khan was one of three players from Pakistan’s squad to test positive for COVID-19. Although he had shown no previous symptoms of the virus, he was advised to go into a period of self-isolation. In July, he was shortlisted in Pakistan’s 20-man squad for the Test matches against England. On 28 August 2020, in the first T20I match against England, Shadab took his 50th wicket in the format.