Considering the increasing global burden of new cancer cases and mortality despite having new avenues open toward chemotherapy, there is a demand for more specific, effective, and safe treatment options for the management of cancer. Although nanoparticulate systems tackle several challenges of cancer treatment, uniquely engineered nanomaterials that can address one-for-all will be desirable. Melanin is a ubiquitous natural-colored pigment that exists in particulate form and has been explored as a biocompatible, biodegradable, safe, and tolerable biomaterial for drug delivery. Melanin-like nanoparticles are artificially created materials prepared using precursors like DOPA, dopamine, or norepinephrine and offer all the benefits of melanin. Having a variety of reactive functional groups like hydroxyl, amine, and carboxyl on the surface offers ease of functionalization for targeted delivery. Being able to change its structural and functional properties in response to external stimuli like radiation, pH, mechanical, magnetic, or electrical stimulus, makes melanin-like nanosystems smart nano-material. Having the advantage of theranostic properties, melanin-like nanomaterials offer a cost-effective, fast, and safe intervention for the management of cancer. This comprehensive review will focus on varieties of melanin and melanin-like materials, applications in chemotherapy and diagnosis, the progress of natural melanin melanin-like nanoparticles in tumor therapy, and their applicability in cancer vaccines.