Gastroesophageal reflux disorders (GERD) along with peptic ulcers are most common health problems in developing countries. The present study aimed to evaluate the raft forming bilayer tablets of sustained release (SR) pantoprazole sodium sesquihydrate (PSS) and immediate release (IR) domperidone maleate (DM). The box behnken design (BBD) was used with three independent and dependent variables. The independent variables were sodium alginate (X1), pectin (X2) and HPMC K100M (X3) while the dependent variables were percentage drug release at 2 (Y2), 4 (Y4) and 8 h (Y8). The powdered blend and prepared granules of SR and IR layer were evaluated for their micromeritic properties. The bilayer tablets were evaluated for thickness, diameter, weight variation, hardness, friability and disintegration time. The alginate-pectin rafts were evaluated for their physical, chemical and swelling properties. The alginate-pectin rafts were characterized by their strength, weight, volume, resilience, reflux resistance, thickness, buffering capacity, neutralizing capacity, floating lag time (FLT) and total floating time (TFT). The alginate and pectin contents within the raft, acid neutralization capacity (ANC), neutralization profile and effect of raft structure on the neutralization profile of alginate-pectin rafts were evaluated. The drug release studies of PSS and DM were carried out in simulated gastric fluid (SGF) pH 1.2. The release kinetics of PSS was determined by different in vitro kinetics models such as zero order, first order, higuchi and Korsmeyer-peppas model. The release kinetics of DM was calculated by zero order, first order and weibull model. The drugs, polymers, bilayer tablets and alginate-pectin rafts were further characterized by Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffractometry (XRD), Differential Scanning Calorimetry (DSC) and Scanning Electron Microscopy (SEM). The High Performance Liquid Chromatography (HPLC) method was developed for the separation of PSS and DM by using C18 column with UV detection at 285 nm in mobile phase as well as in rabbit’s plasma. Assay of the bilayer tablets were performed by already developed HPLC methods in mobile phase as well as in rabbit’s plasma. The optimized formulation R9 was selected on the basis of the physico-chemical characteristics of alginate-pectin raft, release pattern and release kinetics. The accelerated stability studies were performed on optimized formulation R9 for a period of 6 months in stability chamber at 40 ºC temperature and 75±5 % relative humidity. Albino rats were used for the histopathological examination of rat’s stomach by aspirin ulcer induced method of the test and reference formulation. Albino rabbits were used to study the pharmacokinetics of PSS and DM. The prepared bilayer tablets were evaluated for in vivo analysis on healthy albino rabbits using Latin square crossover design. The time to reach maximum concentration of PSS and DM in plasma (tmax), maximum concentration of PSS and DM (Cmax), area under the curve (AUC) from 0-t and 0-∞, area under the first movement curve (AUMC) and mean residence time (MRT) were calculated. The non-compartmental analysis was used to calculate the pharmacokinetic parameters using PK solver Microsoft excel adds in program. The statistical approaches such as descriptive statistics, ANOVA and tukey test were used. In ANOVA all results were considered statistically significant if the p value was less than 0.05. the tukey test was used for means of different groups means. The PSS release at 2 h (Y2), 4 h (Y4) and 8 h (Y8) were ranged from 16.58±0.090-47.78±0.121 %, 45.12±0.102-69.19±0.163 % and 77.45±0.021-98.76±0.071 % respectively. The physical tests of all compressed formulations were within pharmacopoeial limits. The alginatepectin raft was effectively formed in SGF pH 1.2. Observed raft strength of optimized formulation R9 was 6.43±0.019 g, reflux resistance was 2490±0.004 g, thickness of raft was 4.8±0.245 cm and raft resilience was found to be greater than 480 min. Rapid FLT i.e. 55 s was observed and delayed 8 h TFT was observed in R9 optimized formulation. The buffering and neutralizing capacity were 11.20±1.01 meq and 6.5±0.56 meq respectively. The percent contents of sodium alginate and pectin of R9 formulation were found to be 99.20 % and 97.20 % respectively. The ANC, duration of neutralization and nature of R9 alginate-pectin raft were 8.0±0.356 (p value is less than 0.001), 100 min and absorbent. The R9 formulation showed 97.98 % swelling at 8 h (p=0.001). The cumulative percentage release of optimized formulation R9 was found to be 98.76 % for PSS and 98.45% for DM. The PSS followed the first order kinetics and non-fickian diffusion was observed as value of n was greater than 0.7 in korsmeyer-peppas. The release kinetics of DM showed first order release and weibull model indicated the parabolic shape of drug release curve. FTIR spectra of drugs, polymers, bilayer tablets and raft showed no interaction between them. The XRD presented diffraction lines indicates crystalline nature of drugs and disappearance of the diffraction lines in bilayer tablets and raft indicates the drugs were uniformly distributed. DSC thermograms showed endothermic peaks at 250 ºC for PSS and 220 ºC for DM. SEM images showed porous nature of raft. The SEM images of bilayer tablets showed compact nature of tablets and SEM micrograph of the raft showed a highly porous surface, this indicate the diffusion of the drug from raft to the surface. The separation of PSS and DM with good resolution and retention time less than 7 min were attained in mobile phase as well as in plasma. Quadratic outcome of flow rate, composition of mobile phase and pH of buffer on retention time (p ˂0.001) and percentage recoveries of PSS and DM (p =0.0016) were significant. The regression values obtained from linearity curve of PSS and DM were 0.999 and 0.9994 respectively. Percentage recoveries of PSS and DM were ranged from 96.79 to 99.52 % and 95.51 to 99.52 % respectively. The assay of optimized R9 formulation showed the percentage of PSS and DM were found to be 98.89±0.5 % and 99.89±0.5 % respectively. The stability studies showed the bilayer tablets and alginate-pectin rafts were stable under accelerated conditions for up to 6 months. Histopathological studies showed the optimized R9 formulation possessed more antiulcerant activity as compared to the marketed products of PSS. The tmax of the test and reference formulations of DM were 1.00±0.093 h and 1.00±0.120 h respectively. Observed Cmax of the test formulation of DM was 15.11±1.608 µg/ml, which was greater as compared to reference formulation i.e. 12.06±1.234 µg/ml. The AUC(0-t) and AUC(0-∞) of the test formulation of DM was 59.02±2.240 µg×h/ml and 80.15±6.042 µg×h/ml respectively. AUC(0-t) and AUC(0-∞) of the reference formulation of DM was 56.31±1.406 µg×h/ml and 78.94±5.939 µg×h/ml respectively. The tmax for the test formulation of PSS was 8.00±2.135 h (P=0.0001) and the tmax of the reference was 4.00±1.301 h (P=0.0024). The peak plasma concentration of PSS of R9 test and reference formulation were 48.06±0.347 µg/ml and 46.31±0.398 µg/ml respectively. The observed AUC(0-t) of PSS of the R9 test formulation was 525.39±3.437 µg×h/ml which was higher than the AUC(0-t) of reference formulation i.e. 364.63±2.014 µg×h/ml indicating the bioavailability of test formulation was higher than the reference formulation. AUC(0-∞) values of test and reference formulations of PSS were 554.61±8.974 µg×h/ml and 394.14±7.239 µg×h/ml respectively. One-way ANOVA was applied on pharmacokinetic data and value of p was less than 0.05 and results were statistically significant. The obtained p value of tmax and Cmax were 0.0011 and 0.0024 respectively indicates the results are statistically significant. AUC(0-t) and AUC(0-∞) showed p value less than 0.05 indicates the results are statistically significant.