Interleukin (IL)-15 is a potent inducer of differentiation and proliferation of CD8 + T and natural killer (NK) cells, making it a promising candidate for cancer immunotherapy. However, limited efficacy of systemic monotherapy utilizing intravenous IL-15 suggests needs for alternative routes of administration or combination treatment with other therapies. Near-infrared photoimmunotherapy (NIR-PIT) is a highly selective anti-cancer treatment that elicits massive release of tumor antigens and immunogenic signals. Here, we investigated whether intratumoral IL-15 can enhance the effectiveness of cancer cell-targeted NIR-PIT using syngeneic murine tumor models. Intratumoral injection of IL-15 was more effective than intraperitoneal IL-15 in vivo in suppressing tumor growth and inducing intratumoral immune responses. When the efficacy of CD44-targeted NIR-PIT was compared in vivo between IL-15-secreting MC38 (hIL-15-MC38) and parental MC38 tumors, the hIL-15-MC38/NIR-PIT group showed the best tumor growth inhibition and survival. Additionally, the hIL-15-MC38/NIR-PIT group showed significant dendritic cell maturation and significant increases in the number and Granzyme B expression of tumor-infiltrating CD8 + T, NK, and natural killer T cells compared to the treated parental line. Furthermore, intratumoral IL-15 injection combined with CD44-targeted NIR-PIT showed significant tumor control in MC38 and Pan02-luc tumor models. In bilateral tumor models, CD44-targeted NIR-PIT in hIL-15-MC38 tumors significantly suppressed the growth of untreated MC38 tumors, suggesting abscopal effects. Mice that achieved complete response after the combination therapy completely rejected later tumor rechallenge. In conclusion, local IL-15 administration synergistically improves the efficacy of cancer cell-targeted NIR-PIT probably by inducing stronger anti-cancer immunity, indicating its potential as an anti-cancer treatment strategy.