In this study, we conducted a high‐throughput cell‐based immunofluorescence screen to identify commercially available drugs that negatively regulate TBX2 and/or TBX3 levels in TBX2/TBX3‐driven melanoma cells and identify several that exhibit anti‐cancer activity in melanoma and rhabdomyosarcoma by inhibiting TBX2 and/or TBX3. Here, TBX3 is linked to rhabdomyosarcoma.