<p>Skin cancer is an abnormal growth in the epidermis layer of skin. Since the late twentieth century, the rate of skin cancer occurrences has grown significantly. Genetic modification, industrialization, and the rapidly increasing changes in the environment have all contributed to an increase in skin cancer cases. The decreasing popularity of current treatments for skin cancer, such as immunotherapy, surgery, targeted therapy, conventional chemotherapy, and radiotherapy, can be attributed to several factors, including cost, toxicity, and bioavailability. The development of modern drug delivery methods has markedly improved the use of nanoparticles (NPs) in treating skin cancer, particularly poly-lactide-co-glycolide (PLGA). PLGA NPs, ranging from 10 to 400&#xa0;nm, exhibit exceptional skin penetration and controlled drug release, making them ideal for targeted therapy and imaging. By navigating through the cutaneous pores, PLGA NPs overcome skin barrier, enabling sustained drug action and minimizing systemic side effects. Ongoing studies with PLGA NPs demonstrat efficacy in delivering various chemotherapeutic agents and immunotherapies. Despite the significant advantages of PLGA NPs, we still need to address challenges such as biocompatibility and manufacturing costs. Ongoing research aims to optimize PLGA NPs and explore their integration with other therapeutic modalities for personalized skin cancer treatment. This review uniquely focuses on the recent advancements and mechanistic insights of PLGA NP in skin cancer therapy, addressing a gap in current literature. It also offers a comparative perspective with other nanocarriers, highlighting the distinct advantages of PLGA systems and their potential for clinical translation.</p> Graphical abstract <p></p>