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The cholesterol-oxidized metabolite 27-hydroxycholesterol (27-OHC) is synthesized by CYP27A1, which is a key factor in vitamin D and oxysterol metabolism. Both vitamin D and 27-OHC are considered to play important roles in Alzheimer’s disease (AD). The study aims to research the effects of co-supplementation of vitamin D, folic acid, and vitamin B₁₂ on learning and memory ability in vitamin D-deficient mice, and to explore the underlying mechanism. In this study, C57BL/6J mice were fed a vitamin D-deficient diet for 13 weeks to establish a vitamin D-deficient mice model. The vitamin D-deficient mice were then orally gavaged with vitamin D (VD), folic acid (FA), and vitamin B₁₂ (VB₁₂) alone or together for eight weeks. Following the gavage, the learning and memory ability of the mice were evaluated by Morris Water Maze and Novel object recognition test. The CYP27A1-related gene and protein expressions in the liver and brain were determined by qRT-PCR. The serum level of 27-OHC was detected by HPLC-MS. Serum levels of 25(OH)D, homocysteine (Hcy), and S-Adenosylmethionine (SAM) were measured by ELISA. After feeding with the vitamin D-deficient diet, the mice performed longer latency to a platform (<i>p</i> < 0.001), lower average speed (<i>p</i> = 0.026) in the Morris Water Maze, a lower time discrimination index (<i>p</i> = 0.009) in Novel object recognition, and performances were reversed after vitamin D, folic acid and vitamin B₁₂ supplementation alone or together (<i>p</i> < 0.05). The gene expressions of CYP27A1 in the liver and brain were upregulated in the vitamin D-deficiency (VDD) group compared with the control (CON) group (<i>p</i> = 0.015), while it was downregulated in VDD + VD and VDD + VD-FA/VB₁₂ groups compared with the VDD group (<i>p</i> < 0.05), with a similar trend in the protein expression of CYP27A1. The serum levels of 27-OHC were higher in the VDD group, compared with CON, VDD + VD, and VDD + VD-FA/VB₁₂ group (<i>p</i> < 0.05), and a similar trend was found in the brain. The serum 25(OH)D levels were significantly decreased in the vitamin D-deficiency group (<i>p</i> = 0.008), and increased in the vitamin D-supplemented group (<i>p</i> < 0.001). The serum levels of SAM were higher in the B vitamins-supplemented group, compared with CON and VDD groups (<i>p</i> < 0.05). This study suggests that CYP27A1 expression may be involved in the mechanism of learning and memory impairment induced by vitamin D deficiency. Co-supplementation with vitamin D, folic acid, and vitamin B₁₂ significantly reverses this effect by affecting the expression of CYP27A1, which in turn regulates the metabolism of 27-OHC, 25(OH)D, and SAM.