The information on the microbiome’s human pathways and active members that can affect SARS-CoV-2 susceptibility and pathogenesis in the salivary proteome is very scarce. Here, we studied samples collected from April to June 2020 from unvaccinated patients. We compared 10 infected and hospitalized patients with severe (n=5) and moderate (n=5) Coronavirus Disease (COVID-19) with 10 uninfected individuals, including Non-COVID but susceptible individuals (n=5) and Non-COVID and non-susceptible healthcare workers with repeated high-risk exposures (n=5). By performing high-throughput proteomic profiling in saliva samples, we detected 226 unique differentially expressed (DE) human proteins between groups (q-value ≤0.05) out of 2721 unambiguously identified proteins (false discovery rate ≤1%). Major differences were observed between the Non-COVID vs the non-susceptible groups. Bioinformatics analysis of DE proteins revealed human proteomic signatures related to inflammatory responses, central cellular processes, and antiviral activity associated with saliva of SARS-CoV-2 infected patients (p-value ≤0.0004). Discriminatory biomarker signatures from human saliva include cystatins, protective molecules present in the oral cavity, calprotectins, involved in cell cycle progression, and histones, related to nucleosome functions. The expression level of two human proteins related to protein transport in the cytoplasm, named DYNC1 (p-value, 0.0021) and MAPRE1 (p-value, 0.047), correlated with angiotensin-converting enzyme 2 (ACE2) plasma activity. Finally, the proteomes of microorganisms present in the saliva samples showed 4 main microbial functional features related to ribosome functioning that are overrepresented in the infected group. Our study explores potential candidates involved in pathways implicated in SARS-CoV-2 susceptibility although further studies in larger cohorts will be necessary.