The aim the study was to determine the effect of SonoPrep® on the delivery and analgesic effects of EMLA® cream prior to intravenous (iv) cannulation in a tertiary pediatric emergency department. Children aged between 5 and 10 years were enrolled. Patients were randomized to receive either sonophoresis with SonoPrep® or sham sonophoresis followed by application of EMLA® cream for 5 min prior to iv cannulation. The primary outcome measurement was the child's rating of pain immediately after iv placement, using a 10-cm visual analog scale (VAS). Parents or guardians and blinded researchers were additionally asked to rate their perception of the child's pain using the 10-cm VAS and the Wong-Baker Face scale. A total of 42 patients completed the study (21 in the study group, 21 in the control group). The baseline characteristics between the groups were similar. The VAS pain score was significantly lower in children treated with sonophoresis compared with the sham sonophoresis (median (percentiles 25th-75th), 20.0 (10.0-22.5) vs. 60.0 (31.0-87.5); p < 0.001). The parent's perception of the child's pain was significantly lower in the study group vs. the control group by the VAS (median (percentiles 25th-75th), 10.0 (10.0-20.0) vs. 50.0 (15.0-80.0); p < 0.001) and Wong-Baker Face scale (median (percentiles 25th-75th), 2.0 (2.0-2.0) vs. 4.0 (2.5-4.5); p < 0.001). The researcher's evaluation of the child's discomfort was also significantly lower in the study group (2.0 (1.0-3.0) vs. 4.0 (2.5-4.5); p < 0.001). The application of sonophoresis using SonoPrep® followed by the 5-min application of EMLA® cream showed significant benefit in young children in terms of pain reduction and patient satisfaction.