BACKGROUND: Infantile colic is a common condition affecting healthy infants, characterized by excessive crying and fussiness, causing discomfort for the child and psychological distress for their caregivers, particularly mothers. While the exact cause remains unknown, understanding maternal knowledge and practices regarding colic is crucial for effective management and support. This study aimed to assess Palestinian mothers' knowledge and practices regarding infantile colic, focusing on their understanding of the etiology and management strategies. METHODS: This cross-sectional study involved 450 mothers of infants diagnosed with colic attending pediatric clinics. A face-to-face questionnaire assessed maternal knowledge of the etiology, management strategies, and information sources. Data analysis was conducted using SPSS version 20. Chi-square tests identified any significant associations. RESULTS: The study revealed a wide range of maternal knowledge regarding infantile colic, with a significant proportion of mothers (55.6%) claiming prior understanding of this condition. Mothers relied heavily on family friends (40.2%) and personal experience (35.3%) for information about colic, with less reliance on healthcare professionals (13.3%). Cow's milk allergy (33.8%) and bottle feeding (29.6%) were perceived as risk factors while burping (50.4%) and keeping warm (25.6%) were seen as preventive measures. Surprisingly, few mothers linked maternal anxiety or diet (6.4%) to colic. Popular management strategies included massage (77.3%), wrapping (58.7%), and herbal remedies (53.4%). Notably, only 18.9% of mothers sought professional advice. CONCLUSION: The study findings revealed a limited understanding of infantile colic among Palestinian mothers. This highlights the need for educational interventions. Healthcare providers should be more active in educating mothers and addressing the knowledge gaps.