The study is based on applying Artificial Neural Network (ANN) based machine learning and Response Surface Methodology (RSM) as simultaneous bivariate approaches in developing controlled-release rivaroxaban (RVX) osmotic tablets. The influence of different types of polyethylene oxide, osmotic agents, coating membrane thickness, and orifice diameter on RVX release profiles was investigated. After obtaining the trial formulation data sets from Central Composite Design (CCD), an ANN-based model was trained to get the optimized formulations. The Physiological-based Pharmacokinetic (PBPK) modeling of the predicted formulation was performed by GastroPlus™ to simulate in vivo plasma profiles under fasting and fed conditions. In vitro release tests showed zero-order RVX release for up to 12 h. Using graphical and numerical methods, the predicted formulation generated by the prediction profiler was cross-validated by the CCD-based optimized formulation. Analysis of Variance (ANOVA) findings revealed no significant difference between the predicted and optimized formulations and these formulations have a shelf life of 22.47 and 17.87 months, respectively. The PBPK modeling of RVX push-pull osmotic pump (PPOP) tablets suggested enhanced bioavailability in the fasted (up to 82%) and fed (up to 98.5%) state compared to immediate-release tablets. The results indicated that ANN can be effectively used for osmotic systems due to their complex nature and nonlinear interactions between dependent and independent variables.