Ryan is the most eyebrow-raising omission from Popovic's squad, which includes seven uncapped players, for games against Brazil in Brisbane on September 25 and Townsville on September 28.
The 34-year-old lost his starting spot to young goalkeeper Patrick Beach at the World Cup, then was bizarrely substituted on for the round-of-32 penalty shootout against Egypt.
The Socceroos skipper, capped 105 times, said after that loss he was only told he might replace Beach as extra time kicked off - though Popovic has since insisted Ryan knew that was a possibility pre-match.
Levante goalkeeper Ryan has been omitted despite a strong start to the La Liga season.
"We know what Maty Ryan is to Australian football," Popovic said.
"A player that has a distinguished career - continues to have one - over 100 caps.
"But we'd like to have a look at another keeper."
Pressed on how Ryan - who the Socceroos boss also dropped in his first games in charge in 2024 - had taken the omission, Popovic said: "He's good.
"He's the ultimate professional that he is and that's why he's had such a distinguished career.
"He's still available for us and he's certainly not out of the picture moving forward."
Uncapped St Mirren goalkeeper Jacob Chapman replaces Ryan, joining Beach and Paul Izzo in the squad.
Untried left-back Kasey Bos, younger brother of injured star Jordan Bos, has been called up along with fellow untested defender Dylan Leonard, 19.
Former A-League sensations Marcus Younis (Brondby IF) and Eli Adams (Gamba Osaka) earn maiden call-ups alongside Kealey Adamson (QPR), Chapman and Yaya Dukuly (NK Celje) after impressive stints overseas.
"They've been rewarded for the hard work they've put in to get an opportunity overseas," Popovic said.
"They've had to go through the struggles when you go outside of your comfort zone.
"You go through the ups and downs - not playing, playing, injuries, and that helps you grow.
"And these players get mentally tougher, they know how to handle the difficult situations in games and I believe they all deserve an opportunity."
Sixteen players from the 26-man World Cup squad return.
Star left-back Jordan Bos (knee) and central defender Cam Burgess (Achilles) are unavailable.
Cristian Volpato (hamstring) is sidelined with injury.
The Sassuolo attacker was last week fined $722 for driving with cocaine in his system in July. Volpato has maintained his innocence and will challenge the charges in court.
Riley McGree and Patrick Yazbek return after missing the World Cup through injury while Alex Robertson has been recalled.
Cameron Devlin, Nishan Velupillay, Mathew Leckie, Ajdin Hrustic, Kai Trewin and Awer Mabil have been omitted.
Aziz Behich is the only A-League Men player in the squad.
The Socceroos could have played up to four games this window but have settled for two, which Popovic said allowed players to get back to their clubs.
"We feel that with the games in November, we'll be ready for the Asian Cup," he said.
SOCCEROOS SQUAD
Goalkeepers: Patrick Beach, Jacob Chapman*, Paul Izzo
Defenders: Kealey Adamson*, Aziz Behich, Kasey Bos*, Alessandro Circati, Milos Degenek, Jason Geria, Lucas Herrington, Jacob Italiano, Dylan Leonard*, Harry Souttar
Midfielders: Jackson Irvine, Riley McGree, Connor Metcalfe, Aiden O'Neill, Paul Okon-Engstler, Alexander Robertson, Patrick Yazbek
Forwards: Eli Adams*, Yaya Dukuly*, Nestory Irankunda, Mohamed Toure, Tete Yengi, Marcus Younis*
* Denotes uncapped
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