Zerumbone has been reported to maintain the anti-cancer effects in many malignant cells. However, the effect and mechanism of Zerumbone on esophageal squamous cell carcinomas (ESCC) is rarely investigated. Here we report the inhibitory effect of Zerumbone (hereinafter referred to as ZER) on ESCC migration and the underlying molecular mechanism. ZER could inhibit the migration of human esophageal squamous cancer KYSE-30 cells and KYSE-150 cells. ZER induced Rac1 protein down-regulation in a dose- and time-dependent manner. The reduction of Rac1 protein was crucial for ZER-induced inhibition of cell migration, as Rac1 knockdown could enhance ZER-induced inhibition of cell migration. We further demonstrated that the decrease of Rac1 after ZER treatment is via proteasome-dependent degradation pathway, and ZER treatment drastically enhanced ubiquitination of Rac1, which finally caused Rac1 degradation. Collectively, our results indicated that ZER inhibits cell migration by suppressing Rac1 expression. This suppresion is achieved through promoting Rac1 ubiquitination and degradation. Thus, the study raises the possibility of ZER as a potential drug for ESCC due to its ability to inhibit cell migration.