Transdermal drug delivery for local or systemic therapy provides a potential anticancer modality with a high patient compliance. However, the drug delivery efficiency across the skin is highly challenging due to the physiological barriers, which limit the desired therapeutic effects. In this study, we prepared liposome-in-hydrogels containing a tumor targeting photosensitizer IR780 (IR780/lipo/gels) for tumor photothermal therapy (PTT). The formulation effectively delivered IR780 to subcutaneous tumor and deep metastatic sites, while the hydrogels were applied on the skin overlying the tumor or on an area of distant normal skin. The photothermal antitumor activity of topically administered IR780/lipo/gels was evaluated following laser irradiation. We observed significant inhibition of the rate of the tumor growth without any toxicity associated with the topical administration of hydrogels. Collectively, the topical administration of IR780/lipo/gels represents a new noninvasive and safe strategy for targeted tumor PTT.