Midfielder Max Balard, who has thrived since joining Dutch side NAC Breda this season, Sydney FC's Anthony Caceres and Hayden Matthews, and Denmark-based goalkeeper Paul Izzo could all win their first caps.
There are eight changes from Popovic's last squad, with Hibernian striker Martin Boyle back from wrist surgery while Portsmouth forward Kusini Yengi also returns.
There was no place however for 18-year-old winger Irankunda, who has been with Bayern's reserve team and made his international debut in June.
Australia sit second in Asian qualifying Group C on five points from four games, equal with the Saudis and Bahrain and five behind table-topping Japan.
They need to finish in the top two of the six-team group to guarantee their spot at the 2026 World Cup in North America or potentially face another round of qualifying.
"We're in the early stages of this journey as a group and we'll continue to implement the style of play that will be the foundation of our success throughout this cycle," said Popovic, who took over when Graham Arnold quit in September.
"It's an important series of fixtures and we're looking forward to finishing off the year on the right note."
Saudi Arabia head into the clash in Melbourne on Nov. 14 with a new coach after Frenchman Herve Renard replaced sacked Italian Roberto Mancini late last month.
Australia, who have qualified for the last five World Cups, meet Bahrain on Nov. 19.