Calcium and vitamin D co-supplementation is common and widely used, but randomized, controlled trials (RCTs) have yielded inconclusive results concerning its impact on the serum lipid profile. A comprehensive literature search of Medline, Web of Science, Scopus, Embase, Cochrane Central Register of Controlled Trials, and clinical trial registry databases was conducted to identify placebo-controlled RCTs that were published through September 2020 and that evaluated the impact of calcium and vitamin D co-supplementation on total cholesterol (TC), triglycerides (TGs), low- and very-low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol (HDL-C). Standardized mean differences (SMDs) were pooled using random-effects meta-analysis models. Thirteen studies in a total of 2304 participants met the inclusion criteria. Calcium and vitamin D co-supplementation was associated with significant reductions in both TC (SMD, -0.81; 95% CI, -1.35 to -0.27; I2 = 94.6%) and TGs (SMD, -0.50; 95% CI, -0.91 to -0.08; I2 = 91.5%), and with a significant increase in HDL-C (SMD, 1.22; 95% CI, 0.60 to 1.83; I2 = 95.4%). However, calcium and vitamin D co-supplementation were not found to be associated with significantly decreased low-density lipoprotein cholesterol (SMD, -0.39; 95% CI, -0.78 to 0.01; I2 = 90.1%) or very-low-density lipoprotein cholesterol (SMD, -0.01; 95% CI, -0.70 to 0.69; I2 = 82.3%). The findings from the present systematic review and meta-analysis suggest that calcium and vitamin D co-supplementation has a beneficial effect on TC, TG, and HDL-C. Larger-scale, well-designed RCTs are needed to clarify the effect of calcium and vitamin D co-supplementation on all lipid-profile components.