Objective Short-acting β2-agonist (SABA) over-reliance is associated with poor asthma outcomes. As part of the SABA Use IN Asthma (SABINA) III study, we assessed SABA prescriptions and clinical outcomes in patients from six Latin American countries.Methods In this cross-sectional study, data on disease characteristics/asthma treatments were collected using electronic case report forms. Patients (aged ≥12 years) were classified by investigator-defined asthma severity (guided by the 2017 Global Initiative for Asthma) and practice type (primary/specialist care). Multivariable regression models analyzed the associations between SABA prescriptions and clinical outcomes.Results Data from 1096 patients (mean age, 52.0 years) were analyzed. Most patients were female (70%), had moderate-to-severe asthma (79.4%), and were treated by specialists (87.6%). Asthma was partly controlled/uncontrolled in 61.5% of patients; 47.4% experienced ≥1 severe exacerbation in the previous 12 months. Overall, 39.8% of patients were prescribed ≥3 SABA canisters in the preceding 12 months (considered over-prescription). SABA canisters were purchased over the counter (OTC) by 17.2% of patients, of whom 38.8% purchased ≥3 canisters in the 12 months prior. Of patients who purchased SABA OTC, 73.5% were prescribed ≥3 SABA canisters. Higher SABA prescriptions (vs. 1 − 2 canisters) were associated with an increased incidence rate of severe exacerbations (ranging from 1.31 to 3.08) and lower odds ratios of having at least partly controlled asthma (ranging from 0.63 to 0.15).Conclusions SABA over-prescription was common in Latin America, highlighting the need for urgent collaboration between healthcare providers and policymakers to align clinical practices with the latest evidence-based recommendations to address this public health concern.