The prolonged use of conventional disinfectants has intensified microbial resistance, environmental persistence, and human-health concerns. Plant-derived alternatives that act through multi-target mechanisms offer a promising route to mitigate these issues. Sapindus mukorossi pericarp is rich in triterpenoid saponins that function as natural surfactants and exhibit broad-spectrum antimicrobial activity via membrane disruption, biofilm inhibition, and metabolic interference. When combined with nanomaterials or other botanical actives, these saponins display pronounced synergistic effects that further suppress resistance development. This review synthesizes recent advances in green extraction, nano-formulation, and synergistic formulation of Sapindus extracts, and maps their applications in neonatal and maternal care, clinical hygiene, and post-harvest preservation. Current bottlenecks in mechanistic elucidation, scale-up, and regulatory acceptance are discussed, together with future research directions aimed at commercializing robust, low-resistance natural disinfection technologies.