UEFA have "reluctantly" agreed to allow a regular Serie A match between Milan and Como to be staged in the Western Australian capital in February.
European football's governing body also said on Monday they would permit Barcelona and Villarreal to play their December Spanish league clash in Miami.
However, they said they disapproved of clubs taking matches overseas and would work to prevent this becoming a precedent.
FIFA, the world governing body, also have to assent but that is expected to be a formality.
Spain's La Liga have been pursuing their transatlantic vision for almost a decade, emulating the strategy employed by the NFL and NBA to establish themselves in other markets. Spain and Italy have already held Super Cup matches overseas.
The Premier League considered the concept 17 years ago but shelved it due to supporter opposition. Germany's Bundesliga has said it has no plans to take games abroad.
Milan wanted to move their game as the San Siro stadium will be unavailable while the city and stadium prepare to host the Winter Olympics opening ceremony on February 6.
Perth was chosen in part as the club has been cultivating links with Australia for many years, not least due to the huge Italian diaspora present, including playing Roma in Perth in 2024 and the Glory in July this year.
The Roma match was at Optus Stadium, drawing 56,522 fans, and it is anticipated the Rossoneri will play Como at the same venue.
Besides their continental success the club have won 19 domestic titles, most recently in 2022. Their current squad includes former Real Madrid star Luka Modric, of Croatia, USA's Christian Pulisic and Portugal's Rafael Leao.
Como, coached by ex-Arsenal, Chelsea and Barcelona star Cesc Fabregas, have Spain's Alvaro Morata and Brazil's Diego Carlos in their ranks.
For decades many notable foreign clubs have played friendlies in Australia, but this will be the first major competitive club game involving overseas teams.
UEFA's hand appears to have been forced by a court case successfully brought by an American promoter, who wanted to stage matches in the USA.
FIFA withdrew from a legal action brought by Relevent in a Manhattan court 18 months ago and subsequently formed a working group, including UEFA lawyers, that is yet to report. Ironically Relevent has since become a key commercial partner of UEFA.
"League matches should be played on home soil; anything else would disenfranchise loyal match-going fans and potentially introduce distortive elements in competitions," UEFA president Aleksander Ceferin said in a statement.
"While it is regrettable to have to let these two games go ahead, this decision is exceptional and shall not be seen as setting a precedent.
"Our commitment is clear: to protect the integrity of national leagues and ensure that football remains anchored in its home environment."
Serie A president Ezio Simonelli took a different view.
"For us, a contingency due to the unavailability of San Siro stadium has turned into an opportunity to satisfy the many fans of Italian football, who will have the chance to watch the match live in Perth," he said.
With agencies.
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