Effectiveness of nirsevimab against respiratory syncytial virus (RSV) hospitalization during the 2024/2025 season in Spain was estimated using a test-negative design (TND) and hospital-based respiratory infections surveillance data. Children born between 1 April 2024 and 31 March 2025 and hospitalized with severe respiratory infection between the start of the 2024 immunization campaign (regionally variable, between 16 September and 1 October 2024) and 31 March 2025 were systematically RT-PCR RSV-tested within 10 days of symptom onset and classified as cases if positive or controls if negative. Nirsevimab effectiveness ((1 − odds ratio) × 100) was estimated using logistic regression, adjusted for admission week, age, sex, high-risk factors, and regional RSV hospitalization rate. We included 199 cases (68.8% immunized) and 360 controls (86.4% immunized). Overall effectiveness was 65.5% (95% confidence interval: 45.2 to 78.3). Effectiveness was similar among infants born before and after the campaign start (63.6% vs. 70.4%, respectively). We found an unexpected early decrease in effectiveness with increasing time since immunization and age, albeit with wide confidence intervals for some groups. Strong age–period–cohort effects and potential sources of bias were identified, highlighting the need to further explore methodological challenges of implementing the TND in the dynamic population of newborns.