Objectives This systematic review (SR) aimed to summarise and critically appraise available evidence about the association between the synergistic consumption of alcohol and tobacco and the occurrence of oral squamous cell carcinoma (OSCC). Materials and methods Observational studies investigating the association between the synergistic consumption of alcohol and tobacco and OSCC occurrence were included. Studies were selected in a two-phase process and searches were conducted on five main electronic databases, complemented by three grey literature databases. Results From 3260 records identified, 33 articles were included for qualitative analysis, of which 15 were included in the meta-analyses. Overall, the synergistic consumption was positively associated with the occurrence of OSCC (odds ratio OR = 5.37; 95% confidence interval 95%CI = 3.54–8.14). Increased odds for OSCC occurrence were observed regarding the synergistic consumption of alcohol and smoked tobacco (OR = 4.74; 95%CI = 3.51–6.40), alcohol and smokeless tobacco (OR = 7.78; 95%CI = 2.86–21.14), and alcohol, smoked tobacco, and smokeless tobacco (OR = 16.17; 95%CI = 7.97–32.79). Conclusions According to the results of this SR, the synergistic consumption of alcohol and tobacco (both smoked and smokeless) significantly increased the odds for the occurrence of OSCC. Clinical relevance The knowledge provided by this SR may be useful for a better understanding of differences in the effect of synergistic consumption of alcohol and tobacco products in OSCC development. These data might aid healthcare authorities to develop measures for tobacco and alcohol control considering the needs of their population.