Stroke is a major global disability cause, and genetic variables for multifactorial illnesses like stroke are crucial for precision medicine. The purpose of this study is to see if genetic variants in the MTHFR gene are associated with a higher risk of ischemic stroke among the Egyptian population. A case–control study was conducted at Mansoura University Hospital, involving 100 stroke patients and 150 healthy volunteers as the control group. Peripheral blood genomic DNA was isolated and single-nucleotide polymorphisms were genotyped using ARMS-PCR. The CT and TT genotypes of the C677T gene polymorphism exhibited substantial risks for having stroke disease [(OR 3.856; P ≤ 0.001); (OR 4.026; P ≤ 0.001), respectively]. The T allele was significantly more prevalent among patients compared to controls. (OR 2.517; (P = 0.001)). The over-dominant and dominant models demonstrated a substantial relationship between stroke groups at risk of developing stroke but not the Recessive model. An extensive connection was found between the MTHFR A1298C and stroke danger in three different inheritance models: dominant (CC + CA vs. AA), over-dominant (AA + CC vs AC), and allelic (C allele) (P < 0.001). A highly significant difference in blood pressure, total cholesterol, and triglycerides levels was found between patients and control. While there was no meaningful link discovered between genetic polymorphism with SBP, DBP, TG, LDL, VLDL among stroke group (P > 0.05 for each) except the CC genotype that was significantly associated with lower levels of TC and HDL when compared to CT + TT genotypes. The study evaluates a strong link among MTHFR mutations in genes and the probability to get stroke. The research significantly supports the use of MTHFR ((rs1801133) and (rs1801131) variations in stroke prediction.