The probe, which earlier this year saw the Belgian FA headquarters searched, is looking into suspected money-laundering related to transfers including Mitrovic's 18.5 million euro (13 million pound) move from Anderlecht to St James' Park in 2015.
Under the direction of a Belgian anti-corruption judge, police and tax officials swooped on Tuesday and Wednesday, detaining an agent in Monaco and his assistant in the Belgian city of Liege.
"The facts involve notably money-laundering operations and private corruption in the context of football player transfers," the prosecutor's office said in a statement.
The inquiry is separate from Belgium's so-called "footballgate" scandal, which has resulted in 20 suspects being charged since October 2018, including agents, referees and club officials, in a vast investigation into fraud and match-fixing.
Mitrovic, whose committed, physical style of play won him something of a cult following among Newcastle fans, spent three seasons at the club before moving to Fulham in 2018.
His transfer from Anderlecht -- Belgium's most successful club -- involved the agents Pini Zahavi and Fali Ramadani, the Derniere Heure newspaper reported at the time of the initial raids in April.
Prosecutors have not publicly named anyone connected with the probe, but a judicial source confirmed to AFP in April that the Mitrovic transfer was part of the investigation.
The earlier raids saw officers search the Anderlecht training centre as well as the Belgian FA headquarters and the offices of One Goal Management company which specialises in transfers.
The criminal probe adds to Anderlecht's woes on the pitch, where the 34-time Belgian champions are languishing a lowly 13th in the league with just a single win in their first six games this season.