Low-density lipoprotein receptor-related protein 6 (LRP6) is an important coreceptor in the Wnt/β-catenin upstream signaling pathway. Rs2302685 is a common functional mutation of LRP6 that has been previously associated with reduced alcoholic liver injury among alcoholic liver disease (ALD) patients, and the present research was designed to study the underlying mechanisms of that finding. A total of 107 ALD patients and 138 non-ALD patients were recruited from hospitalized alcoholics in China. Their venous blood samples were collected for DNA extraction and genotyped using Sequenom MassARRAY. We found that the rs2302685 mutation, which impaired the function of LRP6, was present in higher frequency among alcoholics with ALD than those without ALD. We also conducted a mouse model experiment in which LRP6 knockdown mice and LRP6 wild-type mice received daily intragastric doses of ethanol (2.4 g/kg) as well as a larger dose of ethanol (4 g/kg) every 7 days for 28 days. The mouse blood and liver specimens were subsequently collected for laboratory analysis, and cell experiments were performed to compare the inhibition, activation, over-expression, and siRNA of LRP6 in the treatment versus the control HL7702 cells. Expression of the targeted molecules was detected by real-time PCR or western blot analysis. Stably transfected cells with pRL3-CYP2E1 vector were used to further study the underlying mechanisms. The total bile acid (TBA), direct bilirubin, total bilirubin (TBIL), aspartate aminotransferase (AST), mitochondrial aspartate aminotransferase, and AST/ALT values were significantly lower in carriers of the rs2302685 mutation than in the wild-type patients, by 63.4, 60.6, 82.1, 44.8, 45.7, and 21.4%, respectively. Compared to the LRP6 wild-type mice, the LRP6 knockdown mice had lower ALT, TBIL, TBA, and ALB/GLO values, as well reduced liver tissue damage, in accordance with their reduced expressions of LRP6, β-catenin, and CYP2E1. In HL7702 cells exposed to ethanol, AST, ALT, lipid accumulation, and ROS generation decreased in cells that were treated with LRP6 inhibitors or siRNA but increased in cells treated with LRP6 activators or over-expressed LRP6. TCF1 was the transcriptional factor most likely to connect the LRP6-Wnt/β-catenin signaling pathway to the regulation of CYP2E1. We concluded that the LRP6 functional mutation rs2302685 contributes to individual differences in susceptibility to alcoholic liver injury related to the Wnt/β-catenin-TCF1-CYP2E1 signaling pathway.