Here, we report six novel, easily accessible BODIPY-based agents for cancer treatment. In contrast to established photodynamic therapy (PDT) agents, these BODIPY-based compounds show additional photothermal activity and their cytotoxicity is not dependent on the generation of reactive oxygen species (ROS). The agents show high photocytotoxicity upon irradiation with light and low dark toxicity in different cancer cell lines in 2D culture as well as in 3D multicellular tumor spheroids (MCTSs). The ratio of dark to light toxicity (phototoxic index, PI) of these agents reaches striking values exceeding 830,000 after irradiation with energetically low doses of light at 630 nm. The oxygen-dependent mechanism of action (MOA) of established photosensitizers (PSs) hampers effective clinical deployment of these agents. Under hypoxic conditions (0.2% O2), which are known to limit the efficiency of conventional PSs in solid tumors, photocytotoxicity was induced at the same concentration levels, indicating an oxygen-independent photothermal MOA. With a PI exceeding 360,000 under hypoxic conditions, both PI values are the highest reported to date. We anticipate that small molecule agents with a photothermal MOA, such as the BODIPY-based compounds reported in this work, may overcome this barrier and provide a new avenue to cancer therapy.