Sublingual buprenorphine is used in the treatment of opioid use disorder (OUD) and neonatal opioid withdrawal syndrome (NOWS). The aim of this study was to develop a full physiologically-based pharmacokinetic (PBPK) model that can adequately describe dose- and formulation-dependent bioavailability of buprenorphine. Simcyp (v21.0) was used for model construction. Linear regression modeling was explored to describe sublingual absorption of buprenorphine across dose. Published clinical trial data not used in model development were used for validation. The PBPK model’s predictive performance was deemed adequate if the geometric means of ratios between predicted and observed (P/O ratios) area under the curve (AUC), apparent clearance (CL/F), peak concentration (C_max), and time to reach C_max (T_max) fell within the 1.25-fold prediction error range. Sublingual buprenorphine absorption was best described by a regression model with logarithmically transformed dose. By integrating this nonlinear absorption profile, the PBPK model adequately predicted buprenorphine pharmacokinetics (PK) following administration of sublingual tablets and solution across a dose range of 2–32 mg, with geometric mean (95% confidence interval) P/O ratios for AUC, CL/F, C_max, and T_max equaling 0.99 (0.86–1.12), 1.04 (0.92–1.18), 1.24 (1.09–1.40), and 1.07 (0.95–1.20), respectively. In conclusion, a fully validated PBPK model was developed that adequately predicts dose- and formulation-dependent buprenorphine PK following sublingual administration. The model forms the foundation on which a fetomaternal PBPK model for buprenorphine can be built. Fetomaternal PBPK modeling will allow conceptualization of prenatal buprenorphine exposure and investigation of its influence on postnatal NOWS severity.