He is set for a new adventure, with Saints Foundation CEO Greg Baker taking on his job.
Boss, who worked for the FA and ESPN in the past, joined the club to boost its commercial revenue.
He is only leaving due to personal reasons and family circumstances and was well liked at the club.
In a new LinkedIn post, Boss said: "After an unforgettable 18-month journey with Southampton Football Club, I am delighted to be handing the baton to Saints’ new Chief Revenue Officer, Greg Baker.
"He is inheriting a talented commercial team that has been doing phenomenal work and has big ambitions for next season in the Premier League and beyond.
"Having worked closely with Greg throughout my time with the club, I can’t think of a better person to help the team realize those ambitions.
"Thank you to all my colleagues and our fans for their warmth and kindness while I have been with this wonderful club. It was so special to be part of our promotion journey this season.
"Once a Saint, always a Saint. I am looking forward to taking some time with my family over the summer while I consider what comes next."