Complex diseases involve multifaceted etiological components, which limit the effectiveness of conventional targeted therapies. Therefore, standard medicinal treatments often face significant challenges and failures when addressing these disease conditions. Furthermore, the growing interest in multidrug resistance (MDR), the occurrence of adverse drug reactions related to use traditional approaches, and the limited clinical efficacy of single-target drug therapy have increased the demand for innovative drug treatments. In this rapidly evolving era, the exploration of multi-target directed ligands (MTDLs) derived from natural products has granted us access to a wide range of compounds with medicinal properties. The allure of these MTDLs lies in their unique ability to minimize side effects from using two medicinal agents, establishing them as the preferred choice for drug developers. MTDLs have been recognized for their extraordinary capacity to collectively hinder multiple pathways implicated in the development of intricate diseases by merging or linking active molecules obtained from these sources. This review delves into promising MTDLs derived from natural products, which modulates diverse biological pathways implicated in complex diseased conditions particularly Alzheimer's disease, diabetes, cardiac disorders and inflammatory conditions.