Hepatocellular carcinoma (HCC) poses a severe threat to human health and economic development. Despite many attempts at HCC treatment, most are inevitably affected by the genetic instability and variability of tumor cells. Arsenic trioxide (ATO) has shown to be effective in HCC. However, time-consuming challenges, especially the optimal concentration in tumor tissue and bioavailability of ATO, remain to be overcome for its transition from the bench to the bedside. To bypass these issues, nanotechnology-based delivery systems have been developed for prevention, diagnosis, monitoring and treatment in recent years. This article is a systematic overview of the latest contributions and detailed insights into ATO-loaded nanocarriers, with particular attention paid to strategies for improving the efficacy of nanocarriers of ATO.