Despite the myriad oral manifestations during COVID-19 and presence of SARS-CoV-2 in saliva, the oral cavity remains an underappreciated site. However recent findings have shown that SARS-CoV-2 can replicate in salivary gland cells, leading to inflammation and tissue destruction. Saliva contains antimicrobial peptides considered integral components of innate immunity crucial for oral health, with the most notable being histatin-5. This peptide is exclusively produced in salivary glands and exhibits unique potent antifungal activity against Candida albicans. In this dissertation, we discovered that destruction of salivary gland by SARS-CoV-2 can compromise histatin-5 production, predisposing patients to oral candidiasis and dysbiosis in the oral microbiome. First, we utilized our novel customized immunoassay to measure salivary histatin-5 levels in a prospective study involving stratified COVID-19 cohorts. Our data indicates a trend showing a decrease in salivary histatin-5 and increase in Candida during COVID-19, persisting post-COVID-19 recovery, potentially contributing to the long COVID-19 syndrome. To provide lacking mechanistic insights into the pathophysiology of salivary gland dysfunction during COVID-19, we performed in situ hybridization coupled with immunofluorescence to co-localize SARS-C0V-2 and histatin-5, respectively, in salivary gland tissue from deceased COVID-19 patients. Our findings indicated diminished or absent histatin presence in salivary gland acini with proliferating SARS-CoV-2 providing the first direct evidence associating SARS-CoV-2 with histatin-5 production. Next, we conducted a comprehensive metagenomic analysis on clinical oral samples and identified potential COVID-19 associated pathologic dysbiotic shifts in the oral microbiome. Lastly, we conducted in-vitro experiments coupled with scanning electron microscopy and confocal imaging to identify the effect of histatin-5 on candida cells and biofilm concluding the antifungal effect of histatin-5 on candida albicans. This clinical study clearly shows the effect of SARS-CoV-2 on oral microbiota, highlighting the importance of understanding and managing the complex dynamics within the oral cavity of COVID-19 patients.