Background: Black garlic is obtained from raw garlic (Allium sativum L.), by a fermentation process, under humidity and heat treatment, showing a high concentration of organosulfur compounds, which have been related to benefits in the prevention or delay of cardiovascular diseases (CVDs). The objective of the research was to evaluate whether long-term consumption of black garlic improves endothelial function and lipid profile in subjects with hypercholesterolemia. Methods: Single center, controlled clinical trial with two branches: Hypercholesterolemia vs. Healthy condition. Sixty-two subjects of both sexes were distributed in two groups, the hypercholesterolemia group (n = 31) (total cholesterol (TC) range 200–300 mg/dL and low-density lipoprotein (LDL)-cholesterol range 135–175 mg/dL) and the healthy group (n = 31). The intervention consisted of the ingestion of 4 cloves of black garlic (12 g) daily for 12 weeks. Results: significant increases in Apolipoprotein (Apo)A1 occurred in both groups: Hypercholesterolemia (Δ 11.8 mg/dL p < 0.001) vs Healthy (Δ 11.1 mg/dL p < 0.001). Besides, significant reductions for endothelial adhesion molecules monocyte chemoattractant protein-1 (MCP-1) (Δ −121.5 pg/mL p = 0.007 vs. Δ −56.3 pg/mL p = 0.015), intracellular adhesion molecule-1 (ICAM-1) (Δ −39.3 ng/mL p < 0.001 vs. Δ 63.5 ng/mL p < 0.001), and vascular cyto-adhesion molecule-1 (VCAM-1) (Δ −144.4 ng/mL p < 0.001 vs. Δ −83.4 ng/mL p = 0.061) were observed, for hypercholesterolemic and healthy subjects, respectively. Conclusions: These data show that black garlic consumption could improve some parameters related to endothelial function and lipid profile, which may have a favorable impact on the risk of CVDs, although more long-term studies are necessary to confirm.