The NFL's first regular-season game at the MCG is likely to clash with the opening week of next year's AFL finals series.
But the AFL has backed the historic deal after being involved in the negotiations.
An obvious scenario is that the NFL game is played at the MCG during the AFL's bye round, before the finals start.
It is the first new major sporting event announcement for the Victorian government since the botched Commonwealth Games project.
Those Games, also to be held next year, will now be in Glasgow and have cost the state government $380 million in compensation.
NFL executive vice president Peter O'Reilly said at Thursday morning's (AEDT) announcement that their first regular-season game in the Asia-Pacific region will be probably be in their week one, which is early September.
"We won't lock into any scheduling here, but the likely scenario would be a week-one game," O'Reilly said.
O'Reilly and Victorian sports minister Steven Dimopolous said the AFL was a key player in the NFL game coming to Melbourne.
"The AFL have been fantastic in terms of these negotiations," Dimopolous said.
O'Reilly then added his appreciation for the AFL's part in the deal.
"This doesn't happen without the AFL's partnership as an important player in this conversation ... that relationship can go beyond just playing (at the MCG)," O'Reilly said.
"This is an incredible league and we can learn from each other. That partnership and relationship is important to us."
The AFL later issued a statement, confirming its support.
"We have a long history of working with governments and venues to support major sporting and cultural events," an AFL spokesperson said.
"We will continue to work together to ensure arrangements are in place for our AFL fans and the wider community to experience the best of both worlds."
The Los Angeles Rams have been confirmed as the host team and their opposition will reportedly be the Philadelphia Eagles.
It is a multi-year deal as the league continues its international expansion.
"Expanding to Melbourne, a beautiful city with a rich sports history, underlines our ambitions to become a global sport and accelerate international growth," NFL commissioner Roger Goodell said.
"Together with the Victorian State Government ... we look forward to making history in what is an important market for the NFL and a significant next step in expanding our international footprint."
The announcement was made in New Orleans, host city of the Super Bowl next Monday morning.
Offensive tackle Jordan Mailata will become the first Australian to play in a winning Super Bowl team if his Eagles beat the two-time defending champion Kansas City Chiefs.
Philadelphia narrowly lost to the Chiefs in the Super Bowl two years ago.
Mailata said he would be hitting up Goodell for tickets if the Eagles play at the MCG.
"It would feel amazing to bring the game Down Under for the growth of the sport but also for the opportunity to play in front of my friends and my family," he said.
"I'd have to ask uncle Roger to pay for all the tickets that I'd have to buy. Maybe half the stadium. We'll see."
The NFL has played 55 regular-season games outside the United States, with London, Madrid and Berlin confirmed as venues this year.
The MCG game is the NFL's first confirmed fixture for 2026.
Victoria premier Jacinta Allan set aside the reputational damage that the Commonwealth Games fiasco had done to the state when she lauded the NFL deal.
"Only Victoria can host an international grand slam, only Victoria can experience the Formula 1 grand prix, only Victoria can break records with the Boxing Day Test - and Victoria is now the only city in Australia to host the NFL," she said.
