Fluctuations in salinity and temperature, among other varying environmental conditions, are stressors in estuaries and may work together to alter the physiological response of organisms that inhabit such environments. Laboratory assessments that investigate how animals respond to multiple environmental stressors can provide an ecological framework for understanding physiological performance across varying conditions. In this study, European green crabs, Carcinus maenas, were collected from Seadrift Lagoon, California, USA (37°54′27.82″N, 122°40′19.56″W) and were lab-acclimated at three different salinity concentrations typical of many estuaries: 15, 25, and 35 PSU at 12 °C (± 1 °C). After acclimation, crabs from each salinity treatment experienced a temperature ramp of 2 °C every 30min until they reached their critical thermal maxima (CTmax). Crabs held at 15 PSU acclimation treatment died at significantly lower temperatures than those acclimated to 25 PSU, demonstrating that the upper thermal tolerance of C. maenas is decreased at lower salinities. Hence, crabs in the northeast Pacific, which are limited to estuarine and brackish waters by marine predators, may be physiologically limited from further expanding their southern range boundary due to the effect of increased temperature on physiological performance. This work took place in March, 2013 and highlights the importance of examining the effect of multiple stressors to understanding what factors may limit or enhance range shifts.