The 57-year-old businesswoman had been with the Hammers for the past 16 years and is credited with leading the negotiations for the deal that saw the Premier League club move from their former Upton Park home to the London Stadium in 2016.
Brady's departure from West Ham marks the end of her business relationship with David Sullivan that dates back almost 40 years.
The businesswoman - who serves as an advisor to Lord Alan Sugar on BBC TV series The Apprentice - persuaded Sullivan to buy Birmingham City in 1993 and she became the club's managing director at the age of just 23.
Brady, who cites West Ham's 2023 Europa Conference League triumph as the highlight of her time with the club, has been - along with Sullivan - the target of fan protests this season with the Hammers battling to avoid relegation from the Premier League.
She told The Times: "It has been a privilege to work alongside the board, management, players, staff and supporters at West Ham United.
"Together we have achieved remarkable milestones, but the highlight for me will always be lifting the UEFA Europa Conference League trophy — a moment that will stay with me forever. I am deeply grateful for the relationships, challenges and opportunities that have shaped my time at the club.
"While this chapter closes, my passion for football and commitment to supporting the next generation of leaders remains undiminished. I wish West Ham United every success for the future and look forward to following their continued achievements with pride."
Sullivan said: "Karren has been an exceptional leader and a key figure in the club’s development over the years. We wish her every success in her future endeavours and thank her for her outstanding contribution over the past 16 years."
West Ham joint-chair Daniel Kretinsky added: "I want to thank Karren most sincerely for our collaboration since 2021, and for all the work she has done in the past for the club. Her contribution to West Ham United’s growth, such as the long-term contract for the London Stadium, shareholders transition and the British record transfer of Declan Rice, has been absolutely essential and not always fully appreciated.
"Karren is also very highly appreciated in the Premier League leadership community and was an excellent representative of our club there. I wish her the best of luck in all future activities."
