Abstract: Arsenic trioxide (ATO) possesses a dual identity as both a component of traditional Chinese medicine and a modern anticancer agent. For a long time, it has demonstrated remarkable efficacy in the treatment of acute promyelocytic leukemia (APL). With the growing number of studies exploring ATO in the field of solid tumor therapy, its diverse mechanisms of action and potential clinical value have attracted widespread attention. ATO can significantly inhibit tumor cell proliferation by inducing multiple modes of cell death, including apoptosis, autophagy, pyroptosis, necroptosis, and ferroptosis. Furthermore, ATO’s regulatory effect on the tumor immune microenvironment provides a new dimension for its antitumor efficacy. Nevertheless, the clinical application of ATO in solid tumors still faces challenges such as low bioavailability, insufficient targeting ability, and toxic side effects. To address these issues, the development of nanocarriers and targeted delivery systems has become a crucial strategy to enhance the therapeutic efficacy of ATO. This article systematically reviews the multiple mechanisms of action of ATO in solid tumors and the latest advances in its nanodelivery technologies over the past five years, explores the potential of ATO-based combination therapy and future development directions, and aims to provide a theoretical basis and practical guidance for the translation of ATO into clinical applications in solid tumor treatment.