He will be replaced by Sir Jon Thompson, who will act as Executive Chair for an interim period while a new CEO is recruited.
Thurston was appointed to the position in March 2017, during his time in post, phase one of construction has reached its peak, creating a workforce of 28,500 including 1,200 apprentices.
Major works for HS2 are currently taking place at over 350 sites between London and the West Midlands.
Along the route, six tunnelling machines have been launched, works on the longest railway bridge in the UK (the Colne Valley Viaduct) are progressing and the 'Marston Box' rail bridge has been successfully slid into place over the M42 motorway.
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Additionally, 19 construction sites are now operating completely diesel-free and nearly one million new trees have been planted alongside the railway.
Commenting on his decision to stand down, Mark Thurston said: "Leading this organisation has been the highlight of my career and a privilege from the first day - the programme has come such a long way and I want to thank everyone who has worked on the project during my time.
"The next 18-24 months will see the project move into an exciting new stage. I have agreed with the Board that someone else should lead the organisation and programme through what will be another defining period for HS2."
Reacting to the announcement, Mark Harper, Secretary of State for Transport, said: "I'd like to thank Mark Thurston for his work over the last six years progressing Britain's most transformative rail project. As well as successfully overseeing the start of construction, he has ensured HS2 has created tens of thousands of skilled jobs and apprenticeships across the country.
"As HS2 enters its next phase, the Government remains committed to unlocking all the benefits of this flagship infrastructure scheme – increasing rail capacity, connecting communities and growing the economy."
