Glutathione reductase (GR) plays a pivotal role in managing oxidative stress, a process crucial for microbial virulence and adaptation, yet it has not been extensively explored in bacteria such as Avibacterium paragallinarum (Av. paragallinarum). This study examined the specific roles of GR in Av. paragallinarum, focusing on how GR modulates the bacterium's response to oxidative stress and impacts its pathogenic behavior. Using gene knockouts together with transcriptomic and metabolomic profiling, we identified an important shift in redox balance due to GR deficiency, which disrupted energy metabolism and weakened the oxidative stress defense, culminating in a notable decline in virulence. In addition, decreased growth rates, reduced biofilm production, and weakened macrophage interactions were observed in GR-deficient strains. Notably, our findings reveal a sophisticated adaptation mechanism wherein the bacterium recalibrated its metabolic pathways in response to GR deficiency without fully restoring virulence. Our in vivo studies further highlight the pivotal role of GR in pathogen fitness. Together, our findings connect GR-mediated redox control to bacterial virulence, thereby furthering the understanding of microbial adaptation and positioning GR as a potential antimicrobial target. Our insights into the GR-centric regulatory network pave the way for leveraging bacterial redox mechanisms in the development of novel antimicrobial therapies, highlighting the importance of oxidative stress management in bacterial pathogenicity.