Biological invasions threaten global biodiversity, with aquatic systems being particularly susceptible. Invasive crayfish drive native crayfish imperilment in North America and worldwide. Despite the probable increase in extreme hydrological events, the synergistic effects from invasive species and drought on crayfish are understudied. The invasion of Faxonius neglectus chaenodactylus in the Spring River drainage (AR, MO) has likely contributed to native crayfish displacement through mechanisms related to stream drying. F. n. chaenodactylus may further expand its range, posing a threat to other native species like Faxonius marchandi, the Mammoth Spring crayfish, a narrow-ranged endemic. We used stream mesocosms to examine (1) effects of invasive species on F. marchandi growth and survival, (2) responses of both species to simulated stream drying, and (3) additive effects of invasion and drought on F. marchandi. Additionally, we assessed differential desiccation tolerance using environmental chambers. We found no significant interaction between drought and competition nor any significant main effects on crayfish mass change or survival; however, interspecific competition significantly reduced length change in F. n. chaenodactylus. All populations showed differential desiccation tolerance, with survival rates varying significantly (p < 0.05) and carapace length (CL) positively influencing survival (p < 0.01). Understanding the effects of drought, invasion, and their interactions on native crayfish is essential, particularly given the potential expansion of an invader and increasing drought intensity from future climate change.