Background Diet and exercise during pregnancy have been used to prevent gestational diabetes mellitus (GDM) with some success. Objective To examine the effectiveness of lifestyle intervention on GDM prevention and to identify key effectiveness moderators to improve the prevention strategy. Search strategy Pubmed, Scopus, Cochrane, and cross‐references were searched. Selection criteria Randomised controlled trials (RCTs) evaluating lifestyle interventions during pregnancy for GDM prevention. Data collection and analysis Two independent reviewers extracted data. A random‐effects model was used to analyse the relative risk (RR) and 95% confidence interval (95% CI). Meta‐regressions and subgroup analyses were used to investigate important moderators of effectiveness. Main results Forty‐seven RCTs involving 15 745 participants showed that diet and exercise during pregnancy were preventive of GDM (RR 0.77, 95% CI 0.69–0.87). Four key aspects were identified to improve the preventive effect: targeting the high‐risk population; an early initiation of the intervention; the correct intensity and frequency of exercise; and gestational weight gain management. Although 24 RCTs targeted women who were overweight or obese, body mass index (BMI) failed to predict the effectiveness of an intervention. Instead, interventions are most effective in high‐incidence populations rather than simply in women who are overweight or obese. Furthermore, exercise of moderate intensity for 50–60 minutes twice a week could lead to an approximately 24% reduction in GDM. Conclusion The best strategy to prevent GDM is to target the high‐risk population predicted by risk evaluation models and to control the gestational weight gain of women through intensified diet and exercise modifications early in their pregnancy. Tweetable Four key effectiveness moderators of lifestyle interventions for GDM prevention. Tweetable Four key effectiveness moderators of lifestyle interventions for GDM prevention.