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Introduction: Alcohol screening, brief advice and referral to treatment (SBIRT) in primary health care is an effective strategy to decrease alcohol consumption at population level. However, there is relatively scarce evidence regarding its economic returns in non‐high‐income countries. The current paper aims to estimate the return‐on‐investment of implementing a SBIRT program in Mexican primary health‐care settings. Methods: Empirical data was collected in a quasi‐experimental study, from 17 primary health‐care centres in Mexico City regarding alcohol screening delivered by 145 health‐care providers. This data was combined with data from a simulation study for a period of 10 years (2008 to 2017). Economic investments were calculated from a public sector health‐care perspective as clinical consultation costs (salary and material costs) and program costs (set‐up, adaptation, implementation strategies). Economic return was calculated as monetary gains in the public sector health‐care, estimated via simulated reductions in alcohol consumption, dependent on population coverage of alcohol interventions delivered to primary health‐care patients. Results: Results showed that scaling up a SBIRT program in Mexico over a 10‐year period would lead to positive return‐on‐investment values ranging between 21% in scenario 4 (confidence interval −8.6%, 79.5%) and 110% in scenario 5 (confidence interval 51.5%, 239.8%). Moreover, over the 10‐year period, up to 16,000 alcohol‐related deaths could be avoided as a result of implementing the program. Discussion and Conclusions: SBIRT implemented at national level in Mexico may lead to substantial financial gains from a public sector health‐care perspective. [ABSTRACT FROM AUTHOR]