This study examines the physicochemical and biological changes in meads produced from five honey types sourced from the Mekong region: Tree Marigold (Tithonia diversifolia, Myanmar), Coffee (Coffea canephora, Vietnam), Kapok (Ceiba pentandra, Cambodia), Rubber (Hevea brasiliensis, China), and Mixed Floral (Thailand). Honey musts were fermented with Saccharomyces cerevisiae at 25 °C for two weeks. After fermentation, meads exhibited lighter coloration, a stable pH (3.5–4.5), and varying bioactivities. All meads showed antimicrobial activity against Escherichia coli, while activity against Staphylococcus aureus and Klebsiella pneumoniae varied by honey source and depended on fermentation. Antioxidant activity ranged from 19.25 to 68.11% inhibition, and peaked in Tree Marigold honey after fermentation. Total phenolic and flavonoid contents fluctuated, with Mixed Floral mead showing the highest post-fermentation phenolic levels. The results of a sensory analysis ranked Tree Marigold mead the highest across taste, mouthfeel, aftertaste, and overall preference. These findings underscore the influence of honey origin and fermentation on the physicochemical, antimicrobial, and sensory properties of mead.