A simple method has been developed and validated for quantitative determination of lumefantrine in antimalarial finished pharmaceutical products using gas chromatography coupled to flame ionization detector. Lumefantrine was silylated with N,O–bis(trimethyl-silyl)trifluoro-acetamide at 70°C for 30 minutes, and chromatographic separation was conducted on a fused silica capillary (HP-5, 30 m length × 0.32 mm i.d., 0.25 μm film thickness) column. Evaluation of the method within analytical quality-by-design principles, including a central composite face-centered design for the sample derivatization process and Plackett–Burman robustness verification of the chromatographic conditions, indicated that the method has acceptable specificity toward excipients and degradants, accuracy [mean recovery = 99.5%, relative standard deviation (RSD) = 1.0%], linearity (=0.9986), precision (intraday = 96.1% of the label claim, RSD = 0.9%; interday = 96.3% label claim, RSD = 0.9%), and high sensitivity with detection limits of 0.01 μg/mL. The developed method was successfully applied to analyze the lumefantrine content of marketed fixed-dose combination antimalarial finished pharmaceutical products.