A successor has not been announced.
Byrne, who has worked for the agency for more than 20 years, will depart after working with the firm's global leadership team through Q1 2018 on a transition.
He joined Weber in 1995 after eight years as the chief press officer for the UK Labour Party, and was promoted to lead the London public affairs practice in 1997. He then became UK CEO in 2000 and added the EMEA region to his duties in 2008.
Global CEO Andy Polansky said: "We are grateful to Colin for his leadership in building Weber Shandwick in the UK and across EMEA. It’s been a pleasure working with Colin for more than two decades. We’ll greatly miss him, his vision and his partnership."
Byrne said: "Working at Weber Shandwick to help build our firm to industry-leading status has been a pleasure and a matter of real professional and personal pride.
"My thanks to our incredible colleagues and clients for two decades of partnership together. I will miss the people, the talent, the pace and the ambition at Weber Shandwick, but given our leading performance and award-winning status, I feel it is a good time to move on with my personal ambitions."
Weber's global revenues rose by 10 per cent last year, one of only two agencies in the top 10 of PRWeek's new Global Agency Business Report to show double-digit growth. UK growth was 11 per cent, meaning the firm consolidated its position as the third biggest agency in the UK.