The Lions made the move official on Wednesday, announcing in a statement Millen has been relieved of his duties as President and CEO.
"I have relieved Matt Millen of his duties effective immediately," said Lions Owner and Chairman William Clay Ford. "I believe that this decision is in the best interest of this organization. I appreciate Matt's efforts. Matt worked tirelessly during his tenure to win, and he would be the first one to tell you that you have to win in this league. It just didn't work out.
"The support of our fans continues to be incredible and they deserve a winner. Every decision we make must focus on that goal, and I believe this decision today will allow this team to move forward in a positive manner."
The tipping point might have been public comments made by the owner's son on Monday.
"I think the fans deserve better," Bill Ford told reporters. "And if it were in my authority, which it's not, I'd make some significant changes."
The team announced executive vice president and COO Tom Lewand will now report directly to the owner on all business, organizational and NFL matters. The Lions said they will evaluate their position after the season with a "thorough and comprehensive evaluation" of their football operations.
"I am very disappointed with where we are as a team after our start this season," William Clay Ford said. "Our sole focus now is preparing for our next game against Chicago. The entire organization must work together and do whatever we can to make this a successful season. Despite our record, it is still early and there is time to turn this season around."
Millen had three years left on a five-year extension he signed in 2005, which was scheduled to run through the 2010 season.
Detroit was routed in each of its first three games this season, falling behind 21-0 twice and 21-3 once en route to lopsided losses. The Lions are off this week.
The 0-3 start dropped Millen to 31-84 overall, giving the Lions at least 10 more losses than any other NFL team over the past seven-plus seasons.
Millen's exit comes more than seven years after the former linebacker and TV analyst took over one of the NFL's most mediocre franchises and made it the worst. Millen's teams won a league-low 31 games since he took over in 2001.
The Associated Press contributed to this report