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Introduction In the UK, short-acting β2-agonist (SABA) overuse in asthma remains common; however, this treatment strategy fails to address underlying inflammation and is associated with increased risk of exacerbations and asthma-related deaths. The SENTINEL Program aimed to identify and address SABA over-use through supported asthma guideline implementation within six English primary care networks (PCNs). Here we report on the effectiveness of SENTINEL to decrease SABA overuse and improve patient outcomes.Methods Data were analysed for adult asthma patients within the six participating PCNs from November 2018 to October 2023. The analysis included three groups: i) the overall asthma population (Overall), ii) patients prioritized for clinic review due to SABA overuse (Review), and iii) patients newly prescribed MART during the review (MART). Outcomes (SABA use, exacerbations defined by acute OCS bursts) were assessed using electronic medical records (EMIS or SystmOne) before and after SENTINEL implementation. EMIS/SystmOne data were pooled where possible but reported separately for MART group and exacerbations due to coding differences. Descriptive statistics were used to describe prescription patterns. Three-level generalized linear mixed models were applied to evaluate changes pre- and post-implementation.Results The Overall, Review, and MART groups included 14,202, 3,208 and 878 patients, respectively. In the Overall group, mean (SD) age was 52.1 (17.9) years, 58.9% were female, and 15.0%, 30.2% and 52.3% were current-, former- or never-smokers, respectively. Most common comorbidities were hypertension (27.5%), frailty (15.2%) and obesity (14.9%). Reduction in SABA prescribing was observed, with adjusted mean (95% confidence interval [CI]) reductions of 1.94 (1.92–1.97) and 4.15 (4.10–4.21) prescriptions per patient per year in Overall and Review groups, respectively (p<0.01). In the MART group, the reduction was 6.34 (6.19–6.48) in EMIS and 6.52 (6.38–6.67) in SystmOne (p<0.01) practices. Exacerbations decreased post-implementation in the Overall group by −7.6 (95% CI −5.8 to −9.4, p<0.01) events per 100 patients per year in EMIS practices, and −3.6 (95% CI −2.7 to −4.4, p<0.01) events per 100 patients per year in SystmOne practices.Conclusions SENTINEL improved prescribing patterns and reduced exacerbations, supporting the importance of implementing evidence-based guidelines into practice to achieve clinical benefits.