Adhering to the Mediterranean diet (MD) and physical activity (PA) public health guidelines have independently been linked to health benefits in adults. These behaviours form essential components of the traditional Mediterranean lifestyle. However, their combined effect on metabolic risk has not been systematically assessed. This systematic review with meta-analysis (PROSPERO; CRD42017073958) aimed to examine, for the first time, the combined effect of promoting the MD and PA compared with no treatment, treatment with MD or PA alone, or a different dietary and/or PA treatment, and estimate its magnitude on metabolic risk factors. Medline, Embase, CINAHL and Web of Science were systematically searched until March 2018 for English language controlled interventions reporting the combined effects of the MD and PA on one or multiple metabolic risk factors in adults. Two researchers independently conducted data extraction and risk of bias assessment using a rigorous methodology. Reporting followed PRISMA guidelines. Quality of reporting and risk of bias were assessed using the CONSORT guidelines and the Cochrane Collaboration’s tool, respectively. Data from 12 articles reporting 11 randomised controlled trials (n
= 1684) were included in the qualitative synthesis; across them, risk of bias was considered low, unclear and high for 42%, 25% and 33% of domains, respectively. Between-study heterogeneity ranged from 44% (triglycerides) to 98% (insulin and high density lipoprotein cholesterol (HDL)-cholesterol). Compared to a control condition, there was strong evidence (p
< 0.001) of a beneficial effect of promoting the MD and PA on body weight (−3.68 kg, 95% CI (confidence intervals) −5.48, −1.89), body mass index (−0.64 kg/m2
, 95% CI −1.10, −0.18), waist circumference (−1.62 cm, 95% CI −2.58, −0.66), systolic (−0.83 mmHg, 95% CI −1.57, −0.09) and diastolic blood pressure (−1.96 mmHg, 95% CI −2.57, −1.35), HOMA-IR index (−0.90, 95% CI −1.22, −0.58), blood glucose (−7.32 mg/dL, 95% CI −9.82, −4.82), triglycerides (−18.47 mg/dL, 95% CI −20.13, −16.80), total cholesterol (−6.30 mg/dL, 95% CI −9.59, −3.02) and HDL-cholesterol (+3.99 mg/dL, 95% CI 1.22, 6.77). There was no evidence of an effect on insulin concentrations. The data presented here provide systematically identified evidence that concurrently promoting the MD and PA is likely to provide an opportunity for metabolic risk reduction. However, due to the high degree of heterogeneity, most likely due to the variation in control group treatment, and the small number of included studies, findings from the pooled analysis should be interpreted with caution. These findings also highlight the need for high quality randomised controlled trials examining the combined effect of the MD and PA on metabolic risk.