We present our perspective on the role of osmolytes in mitigating abiotic stresses such as hypersalinity and sudden temperature changes. While the stabilizing effect of osmolytes on protein tertiary structures has been extensively studied, their direct impact on abiotic stress factors has eluded mainstream attention. Via highlighting a set of recent success stories of a joint venture of computer simulations and experimental measurements, we summarize the mechanistic insights into osmolytic action, particularly in the context of salt stress and combined cold-salt stress at the interface of biomolecular surfaces and saline environments. We stress the importance of chemical specificity in osmolytic activity, the interplay of differential osmolytic behaviors against heterogeneous salt stress, and the capability of osmolytes to adopt combined actions. Additionally, we discuss the potential of incorporating nanomaterial-based systems to enrich our understanding of osmolyte bioactions and facilitate their practical applications. We anticipate that this discourse will inspire interdisciplinary collaborations and motivate further investigations on osmolytes, ultimately broadening their applications in the fields of health and disease.