Haemophilus influenzae is a major causative agent of acute respiratory diseases such as otitis media and pneumonia and drives exacerbations of chronic lung conditions including in COPD and COVID19 patients. Sites of H. influenzae infection are characterized by high levels of inflammation, and the resulting oxidizing environment causes damage to the bacterial cell. This oxidative damage particularly affects sulfur compounds such as methionine which is both a nutrient and essential component of proteins. Using a combination of enzymological, physiological and infection assays we have shown that H. influenzae strains possess a novel, periplasmic stress defence system that consists of one thiol-based methionine sulfoxide reductase, MsrAB, and up to two molybdenum-containing S-oxide reductases, MtsZ and DmsABC. Expression of the components of this system is triggered by exposure to hypochlorite, a reaction product of neutrophil myeloperoxidase, and the thiol-based MsrAB enzyme was required for physical resistance of the bacteria to hypochlorite and led to a small reduction in fitness during infection. Loss of MsrAB also had some immunomodulatory effects (BIRC3, antimicrobial peptides), which may be linked to its ability to repair damage to key Hi outer membrane proteins. In contrast, a loss of either of the Mo-containing S-oxide reductases, MtsZ and DmsABC, caused little or no apparent cellular defect in vitro, but reduced bacterial survival during infections in mice and primary human epithelia by up to 3 orders of magnitude compared to the wildtype. This suggests that these enzymes convert substrates that Hi encounters only during contact with host cells, and compared to related enzymes from non-pathogenic bacteria, both MtsZ and DmsABC showed altered substrate specificities. In the case of MtsZ, we identified methionine sulfoxide as a major substrate, which suggests a possible role of this enzyme in ensuring a supply of methionine for H. influenzae and redox balancing via the respiratory chain. Together, our data indicate that these highly conserved S-oxide reductases form an essential and so far underrecognized element of the adaptation of H. influenzae to survival in its human host.