Electronic nicotine delivery systems (ENDS) heat a liquid solution typically containing propylene glycol, vegetable glycerin, water, nicotine, and flavor chemicals to deliver an aerosol to the user. ENDS aerosols are complex, multi-constituent mixtures of droplets and vapors. Lung dosimetry predictions require mechanistic models that account for the physico-chemical properties of the constituents and thermodynamic processes of the aerosol as it travels through the respiratory tract and deposits in lung airways. In this study, a model formulated to predict ENDS aerosol deposition in the oral cavity and lung airways was linked with a physiologically-based pharmacokinetic (PBPK) model to predict nicotine pharmacokinetics (PK) as a function of product characteristics and puff topography. Predicted plasma nicotine PK compared favorably with available experimental data and captured the rapid increase in plasma levels followed by a clearance phase after ENDS use. E-liquid nicotine concentration and puff duration substantially increased nicotine lung deposition and plasma nicotine levels. Increasing the puff duration from 1 to 5 s while assuming a constant aerosol flow rate resulted in an ∼5-fold increase in nicotine lung deposition (45.0 µg to 243.7 µg) and increased maximum plasma nicotine concentrations from 4.7 ng/mL to 25.0 ng/mL; increasing the e-liquid nicotine concentration from 1 % to 5 % yielded increases in nicotine lung deposition (41.0 µg to 204.5 µg) and maximum plasma nicotine concentration (4.2 ng/mL to 21.1 ng/mL). Model predictions demonstrate the sensitivity of ENDS aerosol lung deposition and plasma nicotine profiles to user behavior and allow for quantification of constituent deposition and nicotine absorption after ENDS use.