Yellow yeast rice (YYR) is a Korean functional food fermented with Aspergillus terreus and contains monacolin K, a cholesterol-lowering ingredient. However, the effects of YYR on lipid metabolism alterations have not been reported until now. In this study, we performed a mass spectrometry-based lipidomic analysis of plasma samples from subjects (31 from the YYR group and 27 from the placebo group) with LDL-C higher than 130 mg dL−1 to investigate the effects of the intake of YYR. Lipidomic profiling showed that the levels of sphingomyelin (SM) were significantly decreased in the YYR intake group compared with the placebo group. The SM level in the YYR intake group showed a significant association with the ApoB/ApoA1 ratio (p = 0.004, r = 0.503), an indicator of the effect of lipid-lowering therapy. This study suggests that global lipidomic profiling could be used to identify changes in lipid metabolism induced by YYR intake and provide information that these lipid changes are associated with improved hypercholesterolemia.