Background: Acute gastroenteritis continues to be a prevalent global health issue among children. The release of interleukin-6 (IL-6) and interleukin-8 (IL-8) from the gastrointestinal tract's epithelial cells is essential for protection against mucosal infections because it triggers the body's inflammatory reactions to infectious pathogens both locally and systemically. Objectives: To investigate serum levels of IL-6 and IL-8 in malnourished children with acute diarrhea. Patients and Methods: A case-control study that included three groups of 30 children each: children with severe acute malnutrition (SAM) and acute diarrhea (SAM-AD), well-nourished children with acute diarrhea (AD), and healthy controls (HC). Participants underwent clinical evaluation and routine laboratory investigations. Serum levels of IL-6 and IL-8 were measured within 72 hours of diarrheal onset using Luminex^Ò Human Premixed Multi-Analyte kit. Results: Serum level of IL-6 in the SAM-AD group (median 1.0 [IQR 1-4.3] pg/ml) was comparable to the HC group (2.2 [1-4.6] pg/ml) but significantly lower than the AD group (12 [3.9-175.6] pg/ml). The SAM-AD group had significantly lower IL-8 levels (16.2 [11-39] pg/ml) than the AD (612 [84.8-800] pg/ml) and HC (157.5 [23.8-298.7] pg/ml) group. IL-6, IL-8, and CRP showed significantly strong correlation with one another (r > 0.67; p <0.001). The presence of fever was significantly associated with higher levels of IL-6, IL-8, and CRP. Conclusion Our study found significantly lower serum levels of IL-6, IL-8, and CRP in malnourished children with acute diarrhea compared to well-nourished children with acute diarrhea, which indicates that malnutrition may impede the acute phase inflammatory response during acute diarrhea.