The study attempted to identify possible overlap between serum cell-reactive proteins (C-rp) and hematological indices as predictors of comorbidity of malaria and septicemia among children attending primary healthcare facilities in Ilorin, Nigeria. One hundred andninety-three children (aged: ≤ 1-15years) presenting with symptoms suggestive of malaria were enrolled. Blood specimens were collected and screened for: Romanowsky, culture, serum C-RP and hematological indices. One hundred and fifteen (59.6%) children had Plasmodium falciparum infections (female 69.0% and male 34.1%). Septicemia was common among 52 (26.9%), but malaria and septicemia co-infection was 42 (36.5%). C-rp levels were low (< 10mg/L) in 41 (35.7%, OR 4.594, CI 2.463-8.571) and high (> 10mg/L) in 74 (64.3%, OR 2.519, CI 1.681-3.775) among the malaria positives (p < 0.05). Children with low C-rp, 8 (15.4%, OR 9.413, CI 4.116-21.531) were positive for septicemia and high C-RP 44 (84.6%, OR 1.694, CI 1.396-2.055), but without malaria, respectively. Similarly, increased C-rp levels were significantly associated with clinical malaria; > 10,000parasites/μL (OR 1.486, CI 1.076-2.054, P < 0.001). Malaria-positive versus negative showed that PCV, C-rp, hemoglobin, platelet, WBC, and neutrophil were statistically significant (P < 0.05). Two bacteria species were identified, viz; Staphylococcus aureus 39 (54.9%) and Escherichia coli 32 (45.1%). The trade-off between sensitivity and specificity occurred at 16.475 cut-off using C-rp and degree of malaria severity as the standard for AUROC. C-rp are inflammatory markers, though non-specificity may be associated with malaria prognosis and severity during malaria-septicemia co-infection.