Background: The number of children residing in grandfamilies is growing worldwide, leading to more research attention on grandparental care over the past decades. Grandparental care can influence child well-being in various forms and the effects vary across contexts. In this systematic review and meta-analysis, we synthesize the evidence on the relation between grandparental care and children's mental health status. Methods: We identified 5,745 records from seven databases, among which 38 articles were included for review. Random effects meta-analyses were used to synthesize evidence from eligible studies. We also examined the variability across study and participant characteristics, including study design, recruitment method, child age, child gender, study region, family type, comparison group, and outcome rater. Results: The meta-analysis consisted of 344,860 children from the included studies, whose average age was 10.29, and of which 51.39% were female. Compared with their counterparts, children being cared for by their grandparents had worse mental health status, including more internalizing problems (d = −0.20, 95% CI [−0.31, −0.09], p =.001), externalizing problems (d = −0.11, 95% CI [−0.21, −0.01], p =.03), overall mental problems (d = −0.37, 95% CI [−0.70, −0.04], p =.03), and poorer socioemotional well-being (d = −0.26, 95% CI [−0.49, −0.03], p =.03). The effects varied by study design and child gender. Conclusions: The findings highlight that grandparental care is negatively associated with child mental health outcomes with trivial-to-small effect sizes. More supportive programs and interventions should be delivered to grandfamilies, especially in disadvantaged communities.