AbstractPhotodynamic therapy (PDT) is emerging as a treatment modality for the management of neoplastic disease. Despite considerable clinical success, its application for the treatment of deep‐seated lesions is constrained by the inability of visible light to penetrate deeply into tissues. An emerging alternative approach exploits the fact that many photosensitisers respond to ultrasound, eliciting cytotoxic effects on target cells and tissues; this has become known as sonodynamic therapy (SDT). The objectives of this study were 1) to determine whether the IR‐absorbing dye, indocyanine green (ICG), can be employed as a sonosensitiser and 2) to determine whether ultrasound can be used to enhance ICG‐mediated PDT. Exposing ICG‐treated mouse fibrosarcoma cells to ultrasound at an energy density of 30 J cm−2 decreased cell viability by 65 %. Prior exposure of ICG‐treated cells to light (λ 830 nm) and subsequent treatment with ultrasound led to a 90 % decrease in cell viability. In combination treatments a synergistic effect was observed at lower doses of ultrasound. Microscopic examination of cell populations treated with light or ultrasound demonstrated the production of intracellular reactive oxygen species (ROS). Using a mouse tumour model, treatment with light, ultrasound, or a combination thereof led to respective decreases in tumour growth of 42, 67, and 98 % at day 27 post‐treatment. These results could provide a means of circumventing light‐penetration issues that currently challenge the widespread use of PDT in the treatment of cancer.