Mykura, who was responsible for hit shows including One Born Every Minute, 24 Hours in A&E, Katie: My Beautiful Friends and Seven Dwarves, intends to make an announcement on his future plans in due course.
After being made head of More4 in 2008, Mykura guided the network from the 12th to 8th most-watched digital channel in the UK, gaining particular international acclaim for the True Stories strand.
As Channel 4's head of specialist factual between 2004 and 2008, Mykura gained a reputation for risky commissions, including Diana: The Witnesses in the Tunnel, 9/11: The Falling Man, and the anatomy shows featuring Gunther von Hagens.
He said: "I've loved every minute of my time at Channel 4. The Channel gives such a range of film makers an opportunity to reflect the modern world. It's a great institution and I'm sure it will go from strength to strength under its present leadership."
Channel 4 chief creative officer Jay Hunt added: "Hamish has been an inspiring and dynamic head of documentaries, keeping Channel 4 at the forefront of innovative filmmaking.
"He has a talent for generating programmes that are genuinely creative as well as popular, and reflect every angle of modern Britain."
Channel 4 declined to comment on who will take up Mykura's role, although the speculation is that head of specialist factual Ralph Lee is being lined up by the broadcaster.