The Northern shrimp (Pandalus borealis) is an ecologically and socio-economically important species in the North Atlantic, yet several of its different populations are collapsing due in part to global change drivers. Here, we aimed to elucidate the molecular mechanisms underlying shrimp responses to combined ocean warming (OW) and acidification (OA). Specifically, we profiled the phospholipidome of the abdominal muscle of female shrimp from four origins in the Northwest Atlantic, subjected to an orthogonal design of temperature (2, 6, or 10 °C) and pH (pH 7.75 or 7.40) scenarios. A suite of multivariate analyses revealed a complex interplay between shrimp origin and exposure to combined OW and OA, with OW primarily driving the phospholipidomic response, particularly at 10 °C. Warming to 10 °C altered phospholipids related to membrane thickness and lateral diffusion, and upregulated sphingomyelins. Notably, OA caused subtler effects, dependent on shrimp origin. Specimens from the Gulf of St. Lawrence showed an interactive effect of OW and OA, whilst those from the coasts of Newfoundland and Nova Scotia were not impacted by OA. Our finding has direct implications for prioritising conservation efforts on shrimp populations featuring a higher sensitivity to multiple stressors. Overall, our findings highlight the power of comparative omics to reveal different levels of intraspecific plasticity in the molecular response of marine organisms to future oceanic conditions. Our results will be refined by integrating multiomics and physiological traits within a multilayer framework to gain a comprehensive understanding of the response to global change drivers.