Since the emergence of Zika virus (ZIKV) in Brazil in 2015, 48 countries and territories in the Americas have confirmed autochthonous cases of the disease caused by the virus. The ZIKV-associated neurological manifestations and congenital defects make the development of safe and effective antivirals against ZIKV of utmost importance. Here, we evaluated the antiviral activity of 6-methylmercaptopurine riboside (6MMPr), a thiopurine nucleoside analog derived from the prodrug azathioprine (AZA), against the epidemic ZIKV strain circulating in Brazil. In all the assays, an epithelial (Vero) and an human neuronal (SH-SY5Y) cell line were used to evaluate the cytotoxicity and the effective concentrations of 6MMPr against ZIKV. The levels of ZIKV RNA, viral infectious titer and the percentage of infected cells at the presence or absence of 6MMPr was used to determine the antiviral efficacy. We show that 6MMPr decreased ZIKV production by more than 99% in both cell lines in a dose- and time-dependent way. Interestingly, 6MMPr was 1.6 times less toxic to SH-SY5Y cells compared to Vero cells, presenting a 50% cytotoxic concentration (CC50) of 460.3 µM and 291 µM, respectively. The selectivity index of 6MMPr for Vero and SH-SY5Y cells was 11.9 and 22.7, respectively, highlighting the safety profile of the drug to neuronal cells. Taken together, our results identify, for the first time, the thiopurine nucleoside analog 6MMPr as promising antiviral candidate against ZIKV that warrants further in vivo evaluation.