This dataset includes the untargeted proteomic quantification data for the annelid Neoleanira tetragona collected along the Lower Estuary and Gulf of St. lawrence, in which an oxygen concentration exists along the bottom waters, from the Gulf to the head of the lower St. Lawrence Estuary. ABSTRACT: Dissolved oxygen is a major environmental driver in aquatic environments, and its decline in the global ocean over recent decades threatens marine fauna, particularly benthic invertebrates. These organisms, often sessile or sedentary, cannot escape persistent environmental hypoxia and must rely on the adjustment of physiological mechanisms, such as energy metabolism and cell functioning pathways, underpinning their ability to cope with these challenging conditions. However, the molecular bases of such mechanisms, particularly under in situ conditions, are yet poorly understood. Here, we characterised the proteomic profile of the annelid Neoleanira tetragona, a species widespread in the North Atlantic Ocean, across the permanent deoxygenation gradient of the Estuary and Gulf of St. Lawrence (EGSL). Specifically, whole specimens were collected from four regions of the EGSL deoxygenation gradient and were analysed using high-resolution LC-MS/MS with a shotgun proteomics approach. Region pairwise comparisons through linear models (LIMMA) showed no differentially abundant proteins, but generalised linear latent variables models identified 59 proteins with differential abundance linked to environmental oxygen and/or food availability. An overrepresentation of tricarboxylic acid cycle via citrate synthase activity was supported in response to low oxygen and high food availability for the annelid. Our results suggest that N. tetragona possesses a compensatory mechanism to cope with the in situ persistent deoxygenation, which involves the accumulation of key proteins that are responsible for maintaining steady energy metabolism under in situ persistent deoxygenation. Our findings contribute to shed light on physiological strategies that benthic marine invertebrates can employ to cope with ongoing and future environmental challenges.