Background: The use of proton pump inhibitors (PPIs) in older adults is high, often inappropriate, and may cause harm. Deprescribing is defined as the reduction, withdrawal, or discontinuation of inappropriate medication. Objective: We conducted a systematic review to determine the effectiveness of interventions to deprescribe inappropriate PPIs in older adults. Methods: We searched MEDLINE, PubMed, Embase, the Cochrane Library, ProQuest Dissertations and Theses Global, and Google from inception to January 2017 for randomized and non-randomized studies describing the outcomes of interventions to deprescribe inappropriate PPIs in older adults (mean or median age of ≥65 years). Where available, clinically relevant outcomes were also assessed. Results: We included 21 articles in our review. Six studies demonstrated effective interventions, 11 were inconclusive, and four were ineffective. Effective interventions included a population-wide education and promotion strategy, academic detailing for general practitioners, and inpatient geriatrician-led deprescribing. Methodological issues limited the interpretation of several studies. Standardization in outcome reporting was lacking, and clinical outcome data were absent. A comparison of intervention effectiveness was not possible because of their heterogeneity, which precluded a meta-analysis. Conclusion: The limited available evidence suggests that some strategies are more successful than others in effectively deprescribing inappropriate PPIs in older adults. However, whether PPI deprescribing translates into better clinical outcomes remains unclear.