Non-Saccharomyces yeasts are promising new probiotics, with effects comparable to the reference probiotic yeast, Saccharomyces boulardii. Candida intermedia, a non-albicans species not considered a common human pathogen, previously demonstrated probiotic potential. This study aimed to evaluate the immunomodulatory effects of C. intermedia in mice vaccinated with inactivated SARS-CoV-2, seeking additional evidence of its probiotic activity. Murine macrophages were stimulated with C. intermedia, followed by mRNA transcription analysis via qPCR. Mice were supplemented with C. intermedia prior to SARS-CoV-2 vaccination. Antibody production was assessed by ELISA, and fecal microbiomes were analyzed using next-generation sequencing. C. intermedia significantly increased Il4 and Il13 expression while decreasing Stat3 in macrophages. Splenocytes from supplemented mice exhibited elevated transcription levels of Tnf, Ifng, Il4, Bcl6, and Stat3 after exposure to stimulatory molecules. These mice showed increased levels of anti-SARS-CoV-2 IgG and sIgA isotypes, along with higher abundances of Bacteroides spp. and Clostridium spp. in their gut microbiome. In conclusion, C. intermedia supplementation modulated the expression of key immune-related genes and enhanced humoral responses in mice. Furthermore, its influence on gastrointestinal microbiota suggests a synergistic effect on vaccine immunogenicity. These findings support the potential of C. intermedia as a novel probiotic candidate with immunomodulatory properties.