Quantification of short-term second-hand exposure to e-cigarette emissions remains limited due to ethical constraints associated with subjective measurements. Alternatively, transient computational fluid dynamics (CFD) simulation coupled with multicompartment physiologically based pharmacokinetic (PBPK) models have been applied to predict indoor, dermal, respiratory, and ocular exposure. Human smoker and nonsmoker bodies and airway models were positioned face-to-face at 0.5 m distance in a displacement-ventilated room. Three PBPK models were integrated within the CFD framework to estimate the absorption fluxes and concentrations of 49 substances in airway mucus, skin surface lipids (SSL), and corneal layers of nonsmoker. Results demonstrated that e-cigarette users exhale, on average, approximately 9–37% of the inhaled mass, depending on puff flow rate. The suspended fraction in indoor air strongly governed by compound solubility in mucus and SSL layers, ranging from ∼90–99% of the exhaled puff. Secondary exposure occurred predominantly via dermal and inhalation pathways, with ocular uptake contributing less but remaining relevant for acute irritation for specific substances. Inhalation exposure was highly sensitive to puff-jet direction, nonsmoker breathing conditions, and diffusivity in air, with values between 0.5–6.8% of total exhaled mass. Downward-oriented puffs increased near-body residence time, enhancing dermal uptake to 8.8% for highly soluble compounds (clothing effects excluded). Overall, for the simulated conditions considered in this study, second-hand exposure reached 4.5–10.2%, demonstrating that even single e-cigarette puff can yield meaningful passive exposure. These findings highlight the need to reassess current regulations restricting e-cigarette use in indoor environments.