A total of 60 DLY pigs (88.16 ± 8.03 kg) were used in a 28-d study to determine the effects of high caloric diet enriched in medium-chain triglycerides (HCD-MCT) and l-arginine (Arg) supplementation on cholesterol and lipid metabolism in a 2 × 2 factorial design. Data were analyzed by ANOVA using the GLM procedures of SPSS with the main effects of diet (10% corn starch vs. 10% coconut oil, coconut oil is enriched in MCT, dietary DE were 3.40 Mcal/kg and 3.87 Mcal/kg), supplemented Arg (0 vs. 1%) and their interaction. HCD-MCT increased serum triacylglycerol (+35.48%), total cholesterol (+34.80%) and HDL-C (+66.05%) levels (P < 0.05), decreased the ratio of LDL-C to HDL-C (−35.24%, P < 0.05). Moreover, HCD-MCT upregulated mRNA expression of 3-hydroxy-3-methylglutaryl coenzyme A reductase (+30.69%) and lecithin cholesterol acyltransferase (+53.06%) in liver (P < 0.05), downregulated mRNA expression of fatty acid synthase (FAS) in backfat (−50.72%, P < 0.05) and peroxisome proliferator-activated receptor-γ (PPAR-γ, −23.93%) in liver (P < 0.05), accompanied by decreased backfat thickness and fat content in liver (−11.91% and −12.76%, P < 0.05). Arg supplementation suppressed gene expression of FAS in backfat (−47.41%, P < 0.05) and PPAR-γ in liver (−19.50%, P < 0.05), elevated gene expression of hormone-sensitive lipase (HSL) and carnitine palmitoyltransferase1 (CPT-1) in backfat (+78.20% and +30.53%, P < 0.05), while reduced backfat thickness (−11.48%, P < 0.05) and fat content in liver (−7.18%, P < 0.05). There was a diet × supplemented Arg interaction observed for FAS, CPT-1 and PPAR-γ mRNA abundance in backfat and liver (P < 0.05), in which pigs fed control diet had less mRNA expression of FAS (−62.00% in backfat, −59.00% in liver) and PPAR-γ (−37.00% in liver), and greater CPT-1 expression (+66.00% in liver) compared with pigs fed HCD-MCT diet. In conclusion, our results indicated that HCD-MCT was helpful to reduce fat deposition in backfat and liver, and improve serum HDL-C concentration. Arg supplementation also prevented fat deposition by regulating lipid metabolism without any effects on cholesterol profile.