Different types of nebulizers, interfaces, and flow rates are used to deliver aerosolized medications to children. The purpose of this study was to determine the effect of nebulizer type, delivery interface, and flow rate on aerosol drug delivery to spontaneously breathing pediatric and infant lung models. A teaching mannequin was attached to a sinusoidal pump via a collecting filter at the bronchi to simulate a spontaneously breathing child (Vt: 250 mL, RR: 20 bpm and Ti: 1 second) and infant (Vt = 100 mL, RR = 30 bpm, Ti: 0.7 seconds). Albuterol sulfate was nebulized with jet (Misty Max 10; Cardinal Health) and mesh (Aerogen Solo; Aerogen) nebulizers using a low-flow nasal cannula (LFNC; Hudson), a high-flow nasal cannula (HFNC; Fisher & Paykel), face mask (FM; Hudson), and mouthpiece (MP; Cardinal Health). While all interfaces were used in the pediatric study, only LFNC, HFNC, and FM were tested in the infant study. The mesh nebulizer was tested at 2, 4, and 6 L/min with LFNC, 4 and 6 L/min with HFNC, and 6 L/min with FM and MP. The jet nebulizer was operated at 6 and 8 L/min with FM and 6 L/min with LFNC, HFNC, and MP (n = 5). The drug was eluted from the filter and analyzed by spectrophotometry. Factorial analysis of variance and post hoc comparisons were used for data analysis. P < .05 was considered statistically significant. Delivery efficiency of mesh nebulizers is two to fourfold more than jet nebulizers used with HFNC, FM, and MP. No statistical difference was found between jet and mesh nebulizers used with LFNC in infants (P = .643) and pediatrics (P = .255). Aerosol delivery with MP was the best compared to other interfaces used in pediatrics (P < .05). As the second-best interface in aerosol drug delivery, the delivery efficiency of FM was greater than HFNC (P = .0001) and LFNC (P = .0001). Increasing flow rate with LFNC and HFNC decreased aerosol delivery with the mesh nebulizer in both infants and pediatrics. The type of nebulizer, delivery interface, and flow rate used in the treatment of children affect aerosol drug delivery.