Melanoma is the most aggressive type of skin cancer, with significant risk of fatality. Due to its pigmentation, light-based imaging and treatment techniques are limited to near the tumor surface, which is inadequate, for example, to evaluate the microvascular density that is associated with prognosis. White-light diffuse reflectance spectroscopy (DRS) and near-infrared optical coherence tomography (OCT) were used to evaluate the effect of a topically applied optical clearing agent (OCA) in melanoma in vivo and to image the microvascular network. DRS was performed using a contact fiber optic probe in the range from 450 to 650 nm. OCT imaging was performed using a swept-source system at 1310 nm. The OCT image data were processed using speckle variance and depth-encoded algorithms. Diffuse reflectance signals decreased with clearing, dropping by after 45 min. OCT was able to image the microvasculature in the pigmented melanoma tissue with good spatial resolution up to a depth of without the use of OCA; improved contrast resolution was achieved with optical clearing to a depth of in tumor. These findings are relevant to potential clinical applications in melanoma, such as assessing prognosis and treatment responses. Optical clearing may also facilitate the use of light-based treatments such as photodynamic therapy.