Objectives: This study aimed to examine the prevalence and pattern of adverse events following childhood immunization and the responses of mothers in Ile-Ife, South West Nigeria. Methods: This descriptive cross-sectional study was conducted among 422 mothers of children aged 0 to 24 months attending any of the 3 leading immunization clinics in Ile-Ife, Nigeria.The respondents were selected using the multi-stage sampling technique. Data were collected using a pretested structured interviewer-administered questionnaire and analyzed using IBM SPSS ver. 26.0. The chi-square test was used to test associations, while binary logistic regression was used to determine the predictors of mothers’ responses to adverse events following immunization (AEFIs). A p-value of < 0.05 was considered statistically significant. Results: The mean age of the respondents was 29.99 ± 5.74 years. About 38% of the children had experienced an AEFI. Most mothers believed that the pentavalent vaccine was the most common cause of AEFIs (67.5%). Fever (88.0%) and pain and swelling (76.0%) were the most common AEFIs. More than half of the mothers (53.7%) administered home treatment followingan AEFI. Younger mothers (odds ratio [OR], 2.43; 95% confidence interval [CI], 1.20–5.01), mothers who delivered their children at a healthcare facility (OR, 3.24; 95% CI, 1.08–9.69), and mothers who were knowledgeable about reporting AEFIs (OR, 2.53; 95% CI, 1.04–7.70) weremost likely to respond appropriately to AEFIs. Conclusion The proportion of mothers who responded poorly to AEFIs experienced by theirchildren was significant. Therefore, strategies should be implemented to improve mothers’knowledge about AEFIs to improve their responses.