Background Malaria remains an important cause of morbidity and mortality in Africa. Previous studies that assessed C-reactive protein (CRP) have centered on the conventional method. This study evaluated the usefulness of high-sensitivity CRP (hs-CRP) in malaria diagnosis and morbidity in a pediatric population in Ghana. Methodology A total of 267 subjects (100 microscopically proven nonmalarial parasitaemics as controls and 167 plasmodium parasitaemic subjects as cases), between the ages of 7 months and 18 years, were recruited for this case-control study. Blood samples were collected for malaria parasite density by microscopic examination; full blood count, electrolytes, and liver function tests using an automated analyzer; and hs-CRP levels by sandwich ELISA method. Results The median hs-CRP concentration was lowest in the control group and increased significantly from low to high parasitaemia. The median hs-CRP level was significantly higher in high malaria parasitaemia compared to moderate and low malaria parasitaemia. Increasing hs-CRP cutoff (3.12-4.64 mg/L) presented with increasing specificity (79.3-93.1%) and sensitivity (96.4%-97.4%), except for moderate parasitaemia where a decline in sensitivity (80.9%) was observed. However, hs-CRP had relatively lower PPV but high NPV at low parasitaemia while both the PPV and NPV were moderate in moderate parasitaemia. Conclusion hs-CRP yielded a high sensitivity, specificity, and accuracy for low, moderate, and high-grade malaria, respectively, and thus may serve as an effective supplementary diagnostic and prognostic biomarker for Plasmodium parasite infection. However, hs-CRP might not be readily useful yet for diagnostic purposes in hospitals due to the relatively low PPV and NPV for low and moderate parasitaemia and thus necessitates further studies in larger cohorts.