Pulmonary Arterial Hypertension (PAH) is a condition of increased blood pressure within the arteries of the lung. Vardenafil (VDF) is commonly used for alleviating pulmonary blood pressure but unfortunately; VDF has low bioavailability due to poor solubility and extensive first-pass metabolism after ordinary oral administration. Therefore, in this study, solid dispersion (SD) of VDF was prepared to enhance VDF dissolution rate and then incorporated into lozenges as a buccal dosage form for systemic drug delivery avoiding first-pass effect. Vardenafil solid dispersion (VDF-SD) lozenges (L1 formula) was selected as master formula due to its high release rate. Organ bio-distribution of VDF (20 mg/kg) following VDF-SD lozenges (L1) administration in adult albino female rats was investigated, and showed a significant increase in Cmax (≈11.55 times) and AUC0–4 h (≈11.81 times) of VDF in lung compared to oral administration of VDF suspension (p < 0.0001). In addition, cyclic guanosine monophosphate (cGMP) serum level, used as indicator of VDF in-vivo efficacy, was higher following VDF-SD lozenges (L1) administration, compared to that following oral administration of VDF suspension. This study suggests that administration of VDF as lozenges in the mouth cavity to be a potential alternative to oral route with superior therapeutic effect targeting pulmonary arterial hypertension.