This study evaluated the antiplasmodial activity and chemical constituents of ethanolic leaf extract of Khaya grandifoliola on mice infected with Plasmodium berghei. Twenty-five mice of both sexes (~30–40 g) were divided into five groups of five mice each. Group 1 (normal control) was untreated and uninfected. Groups 2–5 were intraperitoneally inoculated with 2.5 × 10⁷ P. berghei, while group 2 (disease control [DC]) was untreated-infected group, group 3 (standard drug) received a standard drug, artesunate (50 mg kg⁻¹ b.w.) for 4 consecutive days; groups 4 (LEKG50) and 5 (LEKG100) received ethanolic leaf extracts of K. grandifoliola at 50 mg kg⁻¹ b.w. and 100 mg kg⁻¹ b.w., respectively, after establishment of infection. The LD₅₀ was 4,207.5 mg kg⁻¹ b.w. The results showed a reduction in the mean parasite load of LEKG50 and LEKG100 when compared with DC at day 6 postinfection and beyond. Both LEKG50 and LEKG100 recovered in packed cell volume after an initial drop. There were variable changes in the level of lymphocytes, monocytes, eosinophils, and neutrophils in both LEKG50 and LEKG100 throughout the study period. Sixteen constituents were identified by gas chromatography/mass spectrometry analysis, and oleic acid (33.83%) was most prominent.