This work assesses tablets of artemether and lumefantrine in vitro drug interaction with lamivudine or metronidazole. Spectra changes on artemether or lumefantrine vibration bands were evaluated using Fourier transform infrared spectroscopy (FTIR) and analyzed with essential FTIR (eFTIR) software. Instantaneous pH changes and acid buffering capacity in biorelevant media were also determined. USP type-2 dissolution apparatus (paddle) containing Fed State Simulated Intestinal Fluid Version 2 (FeSSIF-V2) was employed for dissolution test. Sample (5 mL) collected at various predetermined time intervals were analyzed simultaneously for artemether and lumefantrine with high performance liquid chromatographic (HPLC) reverse phase (RP) system, at 25oC. Artemether (O-H) stretching vibration was shifted to wavenumber 3387.0 and 3408.22 cm-1 by lamivudine and metronidazole, respectively. There was no significant shift in spectral bands corresponding to the endoperoxide linkage due to both drugs. Lamivudine and metronidazole showed no significant change in the pH of biorelevant media (p __ampersandsigngt; 0.05). The release kinetics in FeSSIF-V2 for artemether changed from Higuchi (R2 = 0.9124) to first order (R2 = 0.9422) due to presence of lamivudine while that of lumefantrine from first order (R2 = 0.9423) to Higuchi due to the metronidazole (R2 = 0.9871). There was no significant level of interaction between lamivudine and metronidazole with the actives of AL tablet in vitro. The drugs therefore can be co-administered without any biopharmaceutical implications.