Objective This systematic review aims to determine the most effective method of treatment to remineralise post-orthodontic white spot lesions (WSLs). Method Six databases were accessed and searched for articles. Screening and selection were conducted according to the PRISMA guidelines using predetermined inclusion and exclusion criteria. Two reviewers independently assessed and extracted identified studies and relevance disagreement was resolved through consensus. Experimental studies were included that involved (i) patients of any age who had WSLs after the removal of fixed appliances, (ii) any treatment to remineralise the WSLs compared with no treatment or a placebo, and (iii) measurement of the changes in enamel mineralisation status after treatment. Eligible articles were assessed for internal bias and underwent narrative synthesis. A meta-analysis using random-effects modelling was performed to calculate a pooled estimate and assess between-study variability using Cochran’s Q and I2. Results The nine articles included in this review were found to have a medium or high risk of bias. The qualitative assessment provided contrasting results between studies. The meta-analysis showed both CPP-ACP – pooled d of -0.28 (N = 5 studies; 95% CI = -0.48- -0.07) – and fluoride – pooled d of -0.25 (N = 4 studies; 95% CI = -0.48- -0.02) – to generate improvement in the enamel mineralisation status, with CPP-ACP producing more consistent results compared with fluoride. Conclusions The meta-analysis found that CPP-ACP and fluoride were effective in reducing post-orthodontic WSLs. Due to the heterogeneity of the included studies with regard to the fluoride concentrations and mode of delivery, the current meta-analysis could not accurately establish which remineralising agent, CPP-APP or fluoride, is more effective. Further high quality studies of long-term duration are required to determine best clinical practice.