Several systematic reviews have described health-promoting effects of serious games but so far no meta-analysis has been reported. This paper presents a meta-analysis of 54 serious digital game studies for healthy lifestyle promotion, in which we investigated the overall effectiveness of serious digital games on healthy lifestyle promotion outcomes and the role of theoretically and clinically important moderators. Findings showed that serious games have small positive effects on healthy lifestyles (g = 0.260,95% CI 0.148; 0.373) and their determinants (g = 0.334, 95% CI 0.260; 0.407), especially for knowledge. Effects on clinical outcomes were significant, but much smaller (g = 0.079, 95% CI 0.038; 0.120). Long-term effects were maintained for all outcomes except for behavior. Serious games are best individually tailored to both socio-demographic and change need information, and benefit from a strong focus on game theories or a dual theoretical foundation in both behavioral prediction and game theories. They can be effective either as a stand-alone or multi-component programs, and appeal to populations regardless of age and gender. Given that effects of games remain heterogeneous, further explorations of which game features create larger effects are needed.