The use of fucoidan, a marine-origin bioactive polymer, is herein proposed as a component of an innovative and effective strategy against melanoma, one of the most aggressive skin cancers. First, fucoidan antitumor activity, in its soluble form, was assessed presenting increased cytotoxicity over melanoma cells when compared to human dermal fibroblasts and keratinocytes. After this antitumor activity validation and trying to develop a more targeted and local strategy aiming to diminish the cytotoxic effects over noncancer cells, fucoidan was immobilized at the surface of an electrospun nanofiber mesh (NFM_Fu), envisioning the development of a therapeutic patch. The maximum immobilization concentration was 1.2 mg mL–1, determined by the Toluidine Blue Assay and confirmed by XPS. Furthermore, NFM_Fu is more hydrophilic than NFM, presenting a contact angle of 36°, lower than the 121° of the control condition. NFM_Fu was able to reduce human melanoma cell viability by 50% without affecting human dermal fibroblasts and keratinocytes. Taken together, these results set the basis for a valuable approach for melanoma treatment.