Germany have been draw in Group C with the Netherlands, Northern Ireland, Estonia and Belarus and the Serbs are in Group B with Portugal, Ukraine, Lithuania and Luxembourg.
But while Serbia boast a modest World Cup pedigree, the Germans bellow success. They have won four of the 21 tournaments since 1930 and have been runners-up on four occasions.
However the hosts enter the match under pressure to atone for a dismal 2018 World Cup where they were eliminated after the group stage for the first time since 1938.
Loew was expected to lose his job for the debacle but in the fall-out since the Russia meltdown, he has ditched experienced Mats Hummels, Jerome Boateng and Thomas Mueller, a troika of Bayern Munich players that helped the side win the 2014 World Cup in Brazil.
He has replaced their 280 caps with neophytes. Loew's hand comprises the 23-year-old Hertha Berlin defender Niklas Stark as well as the 22-year-olds Lukas Klostermann and Maximilian Eggestein from RB Leipzig and Werbder Bremen respectively.
They join a squad that has only Manuel Neuer and Toni Kroos as the survivors from the 1-0 win over Argentina in 2014 in Rio.
"We need to give the young players the feeling that they have our complete and total trust," said Loew on the eve of the friendly against Serbia.
Loew also urged more experienced youngsters such as 23-year-old Niklas Suele and the 24-year-olds Leon Goretzka and Joshua Kimmich to hone their leadership skills.
"They need to take the next step," he said. "Goretzka and Kimmich are guys with clear ideas, ambition and opinions.
"Suele has to take on responsibility. We expect more from him now. He needs to organise and direct proceedings at the back."
Analysts and pundits will be hovering to see whether the men wilt or bloom in the spotlight.
"Loew is going all-in in a high-stakes game of poker," wrote German football magazine Kicker before the game.
Loew, though, maintains he has made the correct decisions.
"Hummels, Boateng and Mueller are all World Cup winners and great players, so the decision was always going to be debated," he said. "But we are facing a new challenge. We need to be quicker, more dynamic and more ambitious.
"I have been doing this job for 14 years, so I know how to deal with pressure and criticism."