Oral cancer is one of the most common malignancies worldwide [1]. Oral squamous cell carcinoma is the most prevalent type and accounts for 90% of oral cancers [2]. Despite great advances in surgical treatment, radiotherapy, and chemotherapy, the high reoccurrence and poor prognosis of oral cancer appear frequently owing to the rapid growth, local invasiveness, and distant metastasis [3–۵]. Thus, exploring the underlying mechanisms of oral cancer growth and metastasis and identifying a potential therapeutic agent for oral cancer are imperative. Reactive oxygen species (ROS) are highly associated with several pathological conditions, including cancers [6]. It is established that cancer cells usually generate a large amount of ROS [7]. ROS can activate Akt signaling responsible for the proliferation and apoptosis evasion in several cancers, including oral cancer [8, 9]. ROS are highly involved in cancer metastasis, which are proposed to be putative mediators or modulators of epithelial-mesenchymal transition (EMT) [۱۰–۱۲]. EMT plays important roles in cancer metastasis and mainly endows cancer cells with invasive phenotypes [13]. During EMT, epithelial cells lose their epithelial markers, such as E-cadherin, and gain the mesenchymal markers, including Vimentin and Snail [14]. Reportedly, Snail is a transcriptional repressor of E-cadherin in tumor cells [15]. Mechanistically, the activation of phosphatidylinositide 3- kinases (PI3K)/Akt pathway is essential for ROS-driven EMT in colon cancer cells; in detail, ROS-dependent Akt activation enhances the expression of Snail and Vimentin and simultaneously reduces E-cadherin expression [16]. ROS is also a critical regulator of angiogenesis that is essential for cancer metastasis [17, 18]. ROS induces the expression of hypoxia-inducible factor 1α (HIF-1α) and increases its stabilization, thereby leading to the upregulation of vascular endothelial growth factor (VEGF) and subsequent angiogenesis [19, 20]. Both extracellular-regulated protein kinases (ERK) and PI3K/Akt pathways greatly contribute to the ROS-enhanced HIF-1α and VEGF during the malignant transformation of human bronchial epithelial cells [21]. Thus, targeting ROS is a potential therapeutic strategy to reduce the malignant phenotypes of oral cancer. Melatonin (N-acetyl-5-methoxytryptamine), which is mainly produced and secreted by the pineal gland, was initially found to be involved in the regulation of chronobiological rhythm [22]. Recently, as a potent antioxidant, melatonin scavenges a variety of free radicals directly and stimulates the activities of antioxidative enzymes indirectly [23, 24]. Melatonin exerts suppressive effects on multiple types of tumors partly depending on free radical scavenging and antioxidative activities [25–۲۷]. Previously, melatonin was utilized as a preventive and curative agent for oral cancers by abolishing oxidative stress [28, 29]. Nevertheless, whether melatonin hampers oral cancer by reducing ROS-increased proliferation, EMT, and angiogenesis remains unknown.