Chemosynthetic symbioses occur worldwide in marine habitats, but comprehensive physiological studies of chemoautotrophic bacteria thriving on animals are scarce. Stilbonematinae are coated by monocultures of thiotrophic Gammaproteobacteria. As these nematodes migrate through the redox zone, their ectosymbionts experience varying oxygen concentrations. Here, by applying omics, Raman microspectroscopy and stable isotope labeling, we investigated the effect of oxygen on the metabolism of Candidatus Thiosymbion oneisti. Unexpectedly, sulfur oxidation genes were upregulated in anoxic relative to oxic conditions, but carbon fixation genes and incorporation of 13C-labeled bicarbonate were not. Instead, several genes involved in carbon fixation, organic carbon assimilation and polyhydroxyalkanoate (PHA) biosynthesis, as well as nitrogen fixation and urea utilization were upregulated in oxic conditions. Furthermore, in the presence of oxygen, stress-related genes were upregulated together with vitamin biosynthesis genes likely necessary to withstand its deleterious effects, and fewer symbionts were detected to divide. Based on this first global physiological study of an uncultured chemosynthetic ectosymbiont, we propose that, in anoxic sediment, its proliferation is powered by anaerobic sulfur oxidation coupled to denitrification, whereas in upper layers it makes use of aerobic respiration to facilitate assimilation of carbon and nitrogen, and to survive oxidative stress. The ectosymbiont’s versatile metabolism is thus well-adapted to exploiting a highly changeable environment. Overall design: rRNA-depleted total RNA was sequenced (RNA-Seq) of symbiotic nematodes (50 per sample) that were incubated for 24 h under 4 different conditions (oxic, hypoxic, anoxic, anoxic-sulfidic)