Aloe-derived polysaccharides (APS) show promising antiviral activity against the SARS-CoV-2 Omicron variant BQ1.1, offering a potential new line of defense for the respiratory epithelium. Recently, two APS formulations, A50 and I50, differing in molecular weight and acetylation, yet sharing a structural backbone like acemannan were characterized. The two compounds were tested in monolayer and pseudostratified human airway epithelial (HAE) cultures and notably, both compounds demonstrated minimal cytotoxicity and low innate immune activation, highlighting their safety profile. When applied topically 30 min before infection in differentiated HAE cells, APS significantly strengthened epithelial barrier integrity, as shown by increased transepithelial electrical resistance (TEER). Viral RNA levels were markedly reduced on both the apical and basolateral surfaces, and viral plaque assays confirmed decreased viral spread. Together, these findings position APS as promising prophylactic agents capable of reinforcing epithelial defenses and limiting SARS-CoV-2 infection, thus offering broad potential against current and emerging respiratory viral threats.