Introduction: Premature infants are at increased risk of developing chronic respiratory diseases, predisposing them to severe infections, such as those caused by respiratory syncytial virus (RSV). Palivizumab reduces the severity of RSV infections in high-risk children; however, its relationship with asthma development in premature infants remains unclear. Objective: This systematic review with meta-analysis aimed to review the literature and assess whether prophylaxis with palivizumab protects premature infants without congenital heart disease from developing asthma. Results: In total, 14 studies met the inclusion criteria, assessing 1,364,238 children; of these, 9,232 received palivizumab. No significant difference in the chance of developing asthma between the groups (odds ratio (OR) of 0.84, 95% CI [0.62 to 1.13], p = 0.1968). Heterogeneity between studies was I ² = 35.6%. Subgroup analysis for children with a family history of atopy showed no significant reduction in asthma risk (OR 0.78, 95% CI: 0.40–1.55, p = 0.3390). Sensitivity analysis confirmed result robustness. IgE levels were similar between the groups (standardized mean difference [SMD] -0.03 [95% CI: -0.30; 0.23], p = 0.8088). Children who received palivizumab were diagnosed younger (SMD -0.24 [95% CI: -0.38; -0.09], p = 0.0014), with lower gestational age (MD -0.75 [95% CI: -1.61; 0.12], p = 0.0915). Conclusions: Palivizumab prophylaxis does not reduce asthma risk in premature children without congenital heart disease. Its primary benefit lies in preventing severe RSV infections, with no direct impact on asthma developing.