Thompson was only appointed to the post last December but has decided to step down after just a year to spend more time with his family.
A club statement confirmed that Thompson wanted "a better work-life balance and believes that he needs to commit his weekends to his wife after a recent health scare".
Thompson, who will assist the club's board in sourcing a successor, said: "I am incredibly proud to have been a part of Hull City at a pivotal point in their history and to have worked with the owners to build a sustainable commercial model to secure the club's future. It is a privilege to have been a part of this great club, however there are times when family takes higher priority and this is one of them."
Hull chairman Assem Allam said: "It's sad to see Nick leave but we understand his family comes first in these circumstances."
Source: PA
Source: PA