IntroductionAmblyopia therapy appears to be most effective in children under the age of 7 years, but results from randomized control trials (RCTs) have shown that occlusion therapy and/or atropine penalization therapy may improve visual acuity in an older age group. Which of these two therapies is the most effective with fewer adverse effects in an older age group has not yet been agreed upon.MethodsWe systematically searched the literature for RCTs that compared atropine penalization therapy and occlusion therapy in terms of their visual acuity outcomes and adverse events and performed a meta-analysis on the visual acuity data obtained. The adverse effects reported and their implications for clinical practice are discussed.ResultsTwo RCTs were identified, with the authors of both concluding that there was no detectable difference between the two therapies for the age groups they studied. The mean difference between atropine penalization and occlusion therapies was calculated to be − 0.01 logMAR (95% confidence interval − 0.07 to 0.03 logMAR) in favor of occlusion therapy, and no statistical difference between the two groups was detected (P = 0.45). Neither study detected a marked difference in terms of reported adverse effects from the two interventions.ConclusionBased on the results of our meta-analysis we conclude that there is no difference in visual acuity outcomes between atropine penalization therapy and occlusion therapy after 17 to 24 weeks of treatment in children aged 7–12 years. Further evidence to determine the efficacy of amblyopia therapy for an older patient population is required before studies comparing atropine penalization and occlusion therapy in patients older than 12 years can be performed. Atropine penalization therapy may cause more frequent minor adverse effects, such as light sensitivity, but in the clinical setting this needs to be balanced with the potential practical benefits of twice-weekly eye drops versus daily occlusion.FundingThe funding for this study was provided by the National Institute for Health Research (NIHR) and Health Education England (HEE).Plain Language SummaryA plain language summary is available for this article.Electronic supplementary materialThe online version of this article (10.1007/s40123-018-0151-9) contains supplementary material, which is available to authorized users.