During his youth, growing up in Luxembourg, he developed a strong interest in insects under the influence of his father, Jos Hoffmann.

[3] Hoffmann and Bruce Beutler were jointly awarded a half share of the 2011 Nobel Prize in Physiology or Medicine for "their discoveries concerning the activation of innate immunity,".

[2] Hoffmann confirmed discovery of phagocytosis done by Eli Metchnikoff, through injection of Bacillus thuringiensis and observation of increase of phagocytes.

[2] In addition, he showed strong correlation between hematopoiesis and antimicrobial defenses by assessing the susceptibility of an insect to the microbial infection after X-ray treatment.

Dorsal gene, critical in dorso-ventral patterning in the early embryo of Drosophila melanogaster was also identified to be in this NF-κB family.

[10] In 2015, Hoffmann signed the Mainau Declaration 2015 on Climate Change on the final day of the 65th Lindau Nobel Laureate Meeting.

The declaration was signed by a total of 76 Nobel Laureates and handed to then-President of the French Republic, François Hollande, as part of the successful COP21 climate summit in Paris.