He joined the Province in 2008 and made his debut - versus Newport Gwent Dragons - in September that year. He made his 100th appearance, against Scarlets, at Kingspan Stadium just over 12 months ago.
Humphreys has played eight times for Les Kiss' men this season, including four starts, and has scored two tries.
The former Ballymena Academy student also enjoyed two successful stints in England with Leicester Tigers (2005-2008) and London Irish (2012-2014).
Commenting on his decision to retire, Humphreys said:
"Unfortunately my body is telling me it's time to stop. I feel blessed to have enjoyed such a long career, the undoubted highlight of which has been achieving 100 caps for my home Province. I would like to thank everyone who has been part of my journey, particularly my wife Jenny, my daughters Anna and Zoe and the rest of my family."
Ulster's Operations Director, Bryn Cunningham, paid tribute to Humphreys:
"Throughout his rugby career, 'Mini Humph' has been one of the stand-out attacking ten's in European Rugby. However, it is possibly his organisational and communication skills with players around him, often unseen by those watching, that made Ian such an influential person to have around the team. Everyone at Ulster Rugby wishes Ian, Jenny and the kids the very best for the future."