Abstract Colorectal cancer (CRC) continues to be a major cause of cancer‐related death globally, and in order to overcome obstacles like drug resistance and tumor recurrence, novel therapeutic approaches are required. Using near‐infrared (NIR) photothermal agents to create localized hyperthermia for tumor ablation, photothermal therapy (PTT) presents a promising minimally invasive approach. In this work, a new synergistic strategy is created by loading indirubin (Indi), a bisindole alkaloid with anti‐cancer properties, onto copper sulfide nanoparticles (CuS NPs) that are synthesized using a chemical reduction method. Fourier‐transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), fluorescence microscopy, dynamic light scattering (DLS), and UV–Vis spectroscopy are used to characterize the resultant nanoparticles (Indi‐CuS NPs). Alongside the successful addition of indirubin, UV–Vis spectroscopy verified NIR absorption appropriate for PTT. SEM and FTIR confirm the structural and chemical integrity of Indi‐CuS NPs, while DLS shows a hydrodynamic size of 281.2 nm and a zeta potential of −3.08 mV. These results indicate that Indi‐CuS NPs offer a promising platform for synergistic photothermal therapy (PTT) and chemotherapy against colorectal cancer (CRC) by combining the anti‐cancer potential of indirubin with the high photothermal efficiency of CuS NPs.