Background: Chronic spontaneous urticaria (CSU) and moderate-to-severe atopic dermatitis (AD) are significant challenges in pediatric populations, negatively impacting quality of life (QoL). Biologic therapies, including omalizumab and dupilumab, showed considerable promise for patients unresponsive to conventional treatments. This study evaluated the real-life efficacy and safety of these biologics in pediatric CSU and AD patients. Methods: A retrospective, monocentric study was conducted enrolling pediatric patients (aged 6–18 years) followed at the “G. Martino” Hospital, University of Messina. This study included patients with CSU unresponsive to antihistamines and those with moderate-to-severe AD refractory to topical therapies. Disease severity and treatment efficacy were evaluated using the Urticaria Activity Score 7 (UAS7) for CSU, the Eczema Area and Severity Index (EASI) for AD, and QoL metrics, including the Dermatology Life Quality Index (DLQI) and numerical rating scales, for pruritus (p-NRS) and sleep (s-NRS), at baseline, 16 weeks, and 52 weeks. Safety was assessed through the monitoring of reported adverse events (AEs). Results: Omalizumab significantly reduced UAS7 scores by 71.9% at 16 weeks and 75.3% at 52 weeks (p < 0.001), with concurrent improvements in c-DLQI. Dupilumab reduced the EASI score by 75.3%, p-NRS by 40%, and s-NRS by 52.9% over 52 weeks, with c-DLQI improving by 72.6%. No severe AEs were observed; mild reactions included injection-site erythema and respiratory symptoms. Conclusions: Omalizumab and dupilumab demonstrated significant efficacy in reducing disease severity and improving QoL in pediatric patients with CSU and AD. Moreover, their safety profile underscores their potential as essential treatments for these conditions.