Background: Growing evidence shows that grape polyphenols can improve cardiovascular risk factors. Although there are clear data supporting a beneficial effect of grape supplementation on blood pressure and glucose metabolism, the effects of grape polyphenols on lipid metabolism are still controversial. Objective: We performed a meta-analysis of randomized controlled trials (RCTs) to assess the effect of grape products on lipid profile. Design: A systematic search was performed in the PubMed, Web of Science, Scopus, and EMBASE databases without any language or publication year restriction. The reference lists of all retrieved articles were manually reviewed. RCTs evaluating the impact of grape products/juice/extracts on lipid profile were included. Difference in total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), oxidized low-density lipoprotein cholesterol (oxLDL-C), apolipoprotein (apo) A, apo B before and after administration of grape products or placebo were expressed as mean differences (MD) with pertinent 95% confidence intervals (95% CI). The impact of clinical and demographic features on effect size was assessed by meta-regression. Results: The administration of grape products is associated with a significant improvement of lipid profile, as evidenced by changes in TC (MD: −7.6 mg/dL (−0.2 mmol/L); 95% CI: −10.8, −4.4; p < 0.001), HDL-C (MD: 1.4 mg/dL (0.04 mmol/L); 95% CI: 0.8, 1.9; p < 0.001, I2 = 74.7%, p < 0.001), LDL-C (−6.3 mg/dL (−0.16 mmol/L); 95% CI: −9.5, −3.0; p < 0.001), oxLDL-C (MD: −4.5 U/L; 95% CI: −7.5, −1.5; p = 0.003, I2 = 90.6%, p < 0.001), apo B (MD: −2.4 mg/dL (−0.05 µmol/L); 95% CI: −4.5, −0.3; p = 0.026), and TG (MD: −14.5 mg/dL (−0.16 mmol/L); 95% CI: −17.7, −11.2; p < 0.001) levels in subjects receiving grape products compared to placebo. With regard to the extent of the lipid-lowering effect, compared to baseline values, the highest reduction was reported for LDL-C (MD: −5.6 mg/dL (−0.14 mmol/L); 95% CI: −9.5, −1.7; p = 0.005) and for oxLDL-C (MD: −5.0 U/L; 95% CI: −8.8, −1.2; p = 0.010, I2 = 0%, p = 0.470). Conclusions: Grape polyphenols exert a favorable effect on lipid profile in humans by significantly reducing plasma levels of LDL-C and oxLDL-C.