Cold is a global common infectious disease accompanied by symptoms such as headache and stuffy nose. Ibuprofen (IBU) and phenylephrine hydrochloride (PE) were commonly used for common cold due to their different effects in relieving fever and the main symptoms such as nasal congestion and high sinus pressure. However, the commercial tablets of IBU and PE have to be administered 2 to 3 times per day due to their short half-life, with inconvenience for patient and fluctuations of plasma concentration. Bilayer tablet technology was utilized to design the IBU-PE sustained release tablets because of the significantly different solubility of IBU and PE in release media. The formulations of IBU layer and PE layer contain different viscosity grades of hydroxypropyl methylcellulose (HPMC) as sustained-release matrix, hydrophilic diluent, and traditional glidant and lubricant. The sustained release bilayer tablet exhibited satisfying sustained release performance with the mechanisms of diffusion and matrix erosion. Compared with the conventional tablets, the IBU-PE sustained release bilayer tablet expressed significantly sustained-release behavior with decreased Cmax and prolonged Tmax in fasted conditions for IBU and PE. Though IBU of IBU-PE sustained release bilayer tablet was bioequivalent to the commercial IBU tablet, the relative bioavailability of PE from the bilayer tablets was 87.49 ± 20.00% (90% confidence interval was 72.3 to 102.5%), indicating bioinequivalence probably due to the "first pass" effect.