Malaria, caused by Plasmodium vivax, remains a significant health issue in northeastern Iraq. This study collected 5 ml of blood samples from 50 malaria patients and 50 healthy controls at Jalawlaa Hospital in Diyala Province. The infection rates were 13% in the 10-24 age group, 22% in the 25-39 group, and 15% in the 40-64 group, with no significant differences in gender or residency. Patients showed elevated levels of P. vivax IgG antibodies (2.14±0.17) compared to the control group (0.09±0.02), with significant increases in IL-18 (16.97±1.04 vs. 1.73±1.73) and TNF-α (18.45±0.81 vs. 1.31±0.31) levels (P≤0.0001). A strong correlation was found between P. vivax IgG antibodies and IL-18 and TNF-α levels (r=0.666, 0.730). ROC analysis showed excellent diagnostic accuracy for P. vivax IgG antibodies, with 98% sensitivity and 100% specificity at a cutoff value of >1.02. Additionally, a mutation in the TNF gene (SNP rs12934561) was identified, with wild TT and CC variations changing to CC, TT, and TC in patients compared to controls. These findings suggest that P. vivax IgG, IL-18, and TNF-α are valuable biomarkers for malaria diagnosis and highlight genetic variations linked to immune responses. Highlights: Malaria caused by Plasmodium vivax identified in northeastern Iraq, affecting various ages. Patients showed high P. vivax IgG, IL-18, and TNF-α levels (P≤0.0001). TNF gene mutation (SNP rs12934561) found, indicating genetic variation in immune response. Keywords: IL-18, TNF-α, Plasmodium vivax, Malaria, Diyala Province/Iraq.