During the 1920s, due to new visa requirements and the restructuring of the city following the Great Thessaloniki Fire of 1917, the consulate was characterized by significant growth.

During this occupation, three of the consulate's Greek employees- David Tiano, Emmanuel Karasso, and John Vafiades – (the two former being of Jewish extraction) were all sent to an internment camp in Thessaloniki.

During the post World War II years the consulate transformed its role in Thessaloniki, reflecting the evolving relationship between America and Greece.

During the 1960s, the consulate began working with an increasing American business presence in the city which accompanied the Greek Economic Miracle.

Thus, during the 1970s, the consulate began to focus more on improving public relations through an active outreach program to neighboring provincial cities in northern Greece.

This decade was a hectic one for the consulate General as it dealt with several drug trafficking cases originating in the Middle East and Africa.