Natural compound-derived chemotherapies remain central to cancer treatment, however, they often cause off-target side effects that negatively impact patients' quality of life. In contrast, antibody-drug conjugates (ADCs) combine cytotoxic payloads with antibodies to specifically target cancer cells. Most approved and clinically investigated ADCs utilize naturally derived payloads, while those with conventional synthetic molecular payloads remain limited. This review focuses on approved ADCs that enhance the efficacy of naturally derived payloads by linking them with antibodies. We provide an overview of the core components of ADCs, their working mechanisms, and FDA-approved ADCs featuring naturally derived payloads, such as calicheamicin, camptothecin, dolastatin 10, maytansine, pyrrolbenzodiazepine (PBD), and the immunotoxin Pseudomonas exotoxin A. This review also explores recent clinical advancements aimed at broadening the therapeutic potential of ADCs, their applicability in treating heterogeneously composed tumors and their potential use beyond oncology. Additionally, this review highlights naturally derived payloads that are currently being clinically investigated but have not yet received approval. By summarizing the current landscape, this review provides insights into promising avenues for exploration and contributes to the refinement of treatment protocols for improved patient outcomes.