Purpose The objective of this study was to design a fixed-dose combination (FDC) tablet with minimal interaction of valsartan, amlodipine, rosuvastatin and ezetimibe to improve medication compliance in patients with hypertension and dyslipidemia and to evaluate its feasibility for development through in vitro dissolution test and pharmacokinetic assessment in humans. Methods The formulation was designed as a bilayer FDC tablet to minimize the interaction of the four drugs based on the results of drug‒drug interaction evaluations in which the drugs were mixed and exposed at 50 °C for 4 weeks. The FDC tablet was then evaluated against the reference listed drug (RLD) products, Exforge® tablet 10/160 mg and Rosuzet® tablet 10/20 mg, through in vitro dissolution studies and in vivo pharmacokinetic studies in humans. Results The in vitro release profiles of valsartan, rosuvastatin and ezetimibe were similar to those of the RLD products. Although the Cmax of ezetimibe in the FDC tablet was slightly higher, there were no significant differences in the area under the plasma drug concentration–time curve (AUC). There were also no notable discrepancies in the Cmax and AUC of the other three drugs. Furthermore, the absence of statistically significant variations in the frequency of adverse events and the lack of serious adverse reactions indicate a comparable safety profile between the FDC and RLD tablets. Conclusion The feasibility of bilayer FDC tablet formulation to improve medication compliance in patients with hypertension and dyslipidemia was demonstrated.