Whereas CD4 ⁺ T cells conventionally mediate antitumor immunity by providing help to CD8 ⁺ T cells, recent clinical studies have implied an important role for cytotoxic CD4 ⁺ T cells in cancer immunity. Using an orthotopic melanoma model, we provide a detailed account of antitumoral CD4 ⁺ T cell responses and their regulation by major histocompatibility complex class II (MHC II) in the skin. Intravital imaging revealed prominent interactions of CD4 ⁺ T cells with tumor debris-laden MHC II ⁺ host antigen-presenting cells that accumulated around tumor cell nests, although direct recognition of MHC II ⁺ melanoma cells alone could also promote CD4 ⁺ T cell control. CD4 ⁺ T cells stably suppressed or eradicated tumors even in the absence of other lymphocytes by using tumor necrosis factor–α and Fas ligand (FasL) but not perforin-mediated cytotoxicity. Interferon-γ was critical for protection, acting both directly on melanoma cells and via induction of nitric oxide synthase in myeloid cells. Our results illustrate multifaceted and context-specific aspects of MHC II–dependent CD4 ⁺ T cell immunity against cutaneous melanoma, emphasizing modulation of this axis as a potential avenue for immunotherapies.