The former player, Leeds Rhinos assistant and Leeds Carnegie coach leaves after less than two years in charge of the former Super League champions.
A club statement read: “It is with much sadness and reluctance the club has received and accepted the resignation of head coach James Lowes, who has stepped down for personal reasons.
“The club puts on record its gratitude for the significant contribution James has made as Head Coach during his 22 months at Bradford Bulls and we wish him every success in the future.
“Matt Diskin with the support of Chev Walker will act as interim head coach as the process of seeking a replacement begins immediately.
“James Lowes has agreed to conduct a complete hand-over to the performance department in preparation for this weekend’s game against Workington Town.”
Lowes said: “This decision has come with a heavy heart and I have had to make this tough call for personal reasons, and I request everyone respects that.
“I would like to personally thank the players, directors, staff and especially, all the supporters of this great club for my time here.”