Recognized as the most dangerous and fatal form of skin cancers, the incidence of melanoma is swiftly increasing in the entire world, and it mostly affects people with a median age of 57 years and with a fair phototype [1,2]. Melanoma is characterized by the dysfunctional proliferation of melanocytes, cells located in the basal layer of the epidermis which produce the melanin pigment, which are essential for skin protection from solar radiation. Excessive exposure to ultraviolet rays following sunbathing or tanning represents the major risk factor of melanoma [3]. Indeed, UVA and UVB rays cause DNA damage in skin cells which leads to specific mutations that, when accumulated or are in excess, may not be sheltered by DNA repair systems [4]. This triggers the development of genetic alterations, such as the tumor suppressor gene TP53 mutation, the CDK inhibitor gene CDKN2A mutation or the activating BRAFV600E mutation [5,6]. The latter is not typically a UV-induced mutation although a potential sunlight-mediated origin has been described [7,8]. The BRAFV600E mutation is harbored by more than 50% of melanoma patients, inducing uncontrolled cancer cell proliferation, migration and metastasis development [9]. In fact, BRAF inhibitors as well as the most recently approved anti-PDL1 and anti-CTLA-4 monoclonal antibodies represent the first line treatment for melanoma cancer patients. Nevertheless, an important percentage of patients become nonresponsive to these treatments, developing tumor resistance and exacerbation [10]. Therefore, there is an increasing interest in finding and characterizing new promising agents that can be proposed as novel therapeutic approaches for the treatment of melanoma in order to overcome tumor resistance and recurrence. In this context, the use of diet-derived phytochemicals has been proposed as an adjuvant therapeutic approach for cancer treatment. Different diet-derived compounds, such as resveratrol, curcumin, apigenin and capsaicin demonstrated potent bioactivities, showing anti-inflammatory, antibiotic and antitumoral effects [11]. In the last few years, plant and food research has been focused on cruciferous-vegetable-derived compounds. In particular, cruciferous vegetables, which include rocket salads, broccoli and cabbage, are rich in isothiocyanates, which are the hydrolysis products of glucosinolate. Importantly, isothiocyanates have been proposed as promising chemopreventive agents for modulating cancer development and progression as demonstrated by multiple in vitro and in vivo approaches [12,13]. 4-(methylthio) butyl isothiocyanate, commonly referred to as erucin (ERU), is the major component derived from rocket salad leaves and was demonstrated to affect the proliferation of different cancer cell lines through different mechanisms of action, such as apoptosis, autophagy, cell cycle arrest and antioxidant effects [14,15,16,17]. Importantly, Citi et al. recently demonstrated that the antiproliferative and proapoptotic effects of ERU in human pancreatic carcinoma cells are ascribed to the ability of ERU to release hydrogen sulfide (H2S) [18,19]. Likewise, our own group, and others, showed that the H2S pathway participates in melanoma progression and demonstrated that exogenous H2S, by means of H2S-releasing molecules, represents a promising therapeutic approach for the management of metastatic melanoma [20,21,22,23,24,25]. In this study, we characterized the therapeutic potential of ERU in human melanoma for the first time by evaluating its ability to modulate the proliferation, migration, ROS production and mitochondrial activity of human melanoma cells in vitro.