Climate change is exacerbating heatwaves, significantly increasing public health risks, including heightened vulnerability to Vibrio vulnificus infections, especially among older adults. While heat stress alone impairs immune regulation and compromises gut integrity, the combined effects of aging and climate-induced heat stress on infectious severity remain insufficiently explored. Using young (12-week-old) and aged (24-month-old) mouse models, we examined how aging and periodic heat stress synergistically influence susceptibility to Vibrio vulnificus by assessing gut microbiome alterations, immune responses, and antibiotic resistance gene dynamics. Heat stress markedly impaired intestinal barrier function, induced significant microbiome shifts, elevated systemic inflammation, and promoted enrichment of antibiotic resistance genes particularly those conferring tetracycline resistance with effects significantly amplified in aged mice. Upon Vibrio vulnificus infection, aged heat-stressed mice demonstrated elevated inflammatory responses, severe intestinal damage, and pronounced immune dysregulation compared to younger counterparts. Gut depletion and probiotic recolonization models further validated microbiota involvement, showing that Roseburia intestinalis significantly reduced heat stress-exacerbated CD4⁺ T-cell immunosenescence in aged mice. Collectively, this study provides robust experimental evidence highlighting the critical interplay between aging and climate-driven heat stress in intensifying infectious disease severity via microbiome–immune axis disruptions, underscoring the need for microbiota-targeted strategies in climate-vulnerable populations.