The present study was aimed to develop and optimize bilayer tablets of isosorbide mononitrate for sustained release (SR) and propranolol hydrochloride for immediate release (IR) by direct compression method. Eudragit® L100, carbopol® and HPMC K15M were used as release retardant in SR layer and cross carmellose was used as super disintegrants. Central composite design was used for SR layer having three independent variables and three dependent variables. The independent variables were percentages of Eudragit® L100 (X1), carbopol® 934 (X2) and HPMC K15M (X3) while the dependent variables were % drug release at 4 h (Y4), 8 h (Y8) and at 12 h (Y12). Propranolol hydrochloride containing IR layer was designed with different concentrations of crosscarmellose sodium and microcrystalline cellulose.Flow properties of the IR powder were also within the limits. Micromeritic properties of powdered materials were evaluated and the direct compression method was used for compression of SR and IR containing bilayered tablets. Prepared bilayer tablets were characterized by various physical tests, swelling behavior, mucoadhesion test and in vitro drug release studies. Fourier Transform Infrared Spectroscopy (FTIR) was used to check the chemical interaction between drugs and excipients. The prepared bilayer tablets were further characterized by Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA) and X-ray Diffractometry (XRD). Model dependent and non-dependent approaches were used for the analysis of release pattern from both layers. High performance liquid chromatography (HPLC) method was developed in mobile phase and in plasma for the simultaneous estimation of isosorbide mononitrateand propranolol hydrochloride. Accelerated stability studies were performed on optimized formulation FSZ10 for a period of 6 months. Pharmacokinetics of isosorbide mononitrateand propranolol hydrochloride were determined in albino rabbits using latin square cross over design by non compartmental analysis. Various statistical parameters such as descriptive statistics and ANOVA were used on data of in-vitro drug release and pharmacokinetic parameters. Powdered blend of all designed formulations were within the limits of official pharmacopoeias. Hardness of tablets of all batches were found to vary from 4.125 to 5.347 kg/cm2. Percentage friability of all formulations were less than 1 %. Dependent variable like Y4 (release of drug at 4 h) was in the ranged from 20 to 62%, Y8 (release of drug at 8 h) ranged from 55 to 84% and Y12 (release of drug at 12 h) ranged from 82 to 99%. 99.96 % release of isosorbide mononitrateform SR layer and 99.96 % release of propranolol hydrochloride was observed form optimized formulation FSZ10. First order release kinetics were followed and non-fickian diffusion was observed in isosorbide mononitrateand propranolol hydrochloride release. The f2 value of FSZ10 and FSZ19 was 67.27 indicating that their release profile was similar to that of the marketed product. Bilayer tablet of FSZ10 formulation showed greatest swelling (98.6 % after 12 h) in phosphate buffer as compared to other formulations. The mucoadhesive strength of optimized formulation FSZ10 was 1.96±0.32 g. FTIR spectra of tablet of optimized formulation FSZ10 showed peaks at 3250cm-1 due to O-H stretching of isosorbide mononitrate , 2900cm1 due to protonation of dimethylamine group of Eudragit® L100, 1713cm-1 due to carbonyl group of Carbopol® 934 and 1110cm-1 due to O-H stretching vibration of HPMC K15M showed the compatibility of drug and polymers in prepared bilayer tablets. The diffractograms of isosorbide mononitrateand propranolol hydrochloride showed many characteristics peaks indicate the crystalline nature but the disappearance of peaks in FSZ10 formulation indicates the drugs was uniformly distributed in the final formulation. Thermogravimetric analysis of isosorbide mononitrateand propranolol hydrochloride showed thermal peaks at 290 0C and 380 0C respectively. Mobile phase consisting of phosphate buffer, acetonitrile and methanol in the ratio of 45:10:45 respectively and pH was adjusted to 3.0. This mobile phase was utilized for analysis through HPLC. 20µl solution of isosorbide mononitrateand propranolol hydrochloride was injected to HPLC system for analysis having flow rate of 1ml/min. Observed peaks of isosorbide mononitrateand propranolol hydrochloride showed worthy symmetry resolution and at 3.901 min and 6.481 min retention times. Limit of detection (LOD) and limit of quantification (LOQ) were found to be 0.529 and 5.04 ppm for propranolol hydrochloride and 2.08 and 5.13 ppm for isosorbide mononitraterespectively. The retention times of isosorbide mononitrateand propranolol were same in mobile phase and in rabbit plasma suggested that the established method was suitable for the pharmacokinetic studies of the isosorbide mononitrateand propranolol hydrochloride. Assay studies showed that bilayer tablet of optimized formulation FSZ10 contained 99.23 % isosorbide mononitrateand 99.78 % propranolol hydrochloride. In pharmacokinetic studies Latin square design was used and obtained results showed the tested formulation possessed better results as compared to the reference formulations. The results of ANOVA showed the value of p was less than 0.05 indicating the results are statistically significant. Cmax were 100.009 ± 0.892 ppm and 101.007 ± 0.872ppm, t1/2 was 53.2 ± 0.003min and 51.2 ± 0.003min respectively, in group A and B respectively receiving ISMN-PH (Isosorbide mononitrate – Propranolol hydrochloride) test formulation and I-P (Isosorbide mononitrate – Propranolol hydrochloride) reference formulation. The results for AUC0-36 and AUMCtotal were 192.92 ± 0.712 and 182.92 ± 0.612µg h/ml, and 58.305 ± 15.901 and 57.355 ± 15.911 µg h/ml in group A and B respectively receiving ISMN-PH and I-P. The volumes of distribution of propranolol hydrochloride and isosorbide mononitratewere 0.0198± 0.0002 L and 0.0188± 0.0002 L respectively. One-way ANOVA was applied on drug release data and value of p was less than 0.05 and outcomes were statistically noteworthy. Reported study will open the new horizons for the formulation development scientists. Bilayered tablets having immediate effects of one layer and sustained release effects of other layer will provide the synergistic effect in the hypertensive patients. In lower income countries like Pakistan, such types of studies are considered important not only for the poor community but also for those patients who are unable to use the multiple dosage forms.