Obesity has become a widespread health issue, often leading to serious conditions like fatty liver disease, type 2 diabetes, and heart disease. A significant factor in obesity is the buildup of triglycerides, with diacylglycerol acyltransferase (DGAT1) being a key enzyme involved in triglyceride synthesis and a potential target for treatment. This study explored the potential of morpholino pyrimidine/pyrimidino-oxazine as DGAT1 inhibitors using computational methods. A library of 250 compounds from PubChem and ZINC databases was docked against DGAT1 (PDB ID: 6VP0), yielding binding energies between −6.0 and −11.6 kcal/mol. ADME and physicochemical assessments narrowed these to the top 20 candidates. A 2D-QSAR model (R2 = 0.928, Q2 = 0.624) was created using known DGAT1 inhibitors and predicted -LogIC50 values for the top compounds showed close alignment. Furthermore, molecular dynamics simulations (100 ns), three sets of short MD run for 25 ns and principal component analysis (PCA) were conducted on the top two hits, PubChem CID155551474 and CID46268159. The results demonstrated stable complexes with DGAT1, with CID155551474 exhibiting superior performance. MMPBSA analysis confirmed binding stability with maximum energy at −300.42 ± 12.41 kJ/mol. This work is the first to suggest morpholino-pyrimidine and pyrimidino-oxazine derivatives as DGAT1 inhibitors, recommending further in vivo studies to confirm therapeutic efficacy.