Our study aimed to analyze the clinical data of a cohort of Egyptian children with cow’s milk protein allergy (CMPA) to explore the epidemiological, clinical characteristics, and risk factors of CMPA. A prospective, multi-center observational cross-sectional study was conducted by assessing the clinical data of infants with CMPA. A total of 317 infants met inclusion criteria, including 175 males (55.2%); the mean age at presentation was 4.2 ± 3.2 months. In our series, artificial feeding was found in 48% of patients, breastfeeding in 22.7%, and 29.3% of infants were mixed fed. 83.6% of patients with CMPA have mild to moderate disease, and 16.4% have severe disease. The most prevalent symptoms were mainly of gastrointestinal tract (GIT) origin, which include diarrhea (57.7%), hematochezia (39.7%), vomiting (30%), and constipation (5%). Skin manifestations included eczema (25.8%) and urticarial (8.2%). Chest wheezes and oral allergy syndrome were found in 7.9% and 4.4%, respectively. Family history of atopy and parent’s and/or sibling’s allergy were found in 60.5% and 27.7%, respectively. Finally, failure to thrive was found in 22.4% of our patients. The multivariate logistic regression analysis of risk factors for CMPA showed that parent’s food allergy (p < 0.001), cesarean section (p < 0.01), and the use of weaning food before four months of age (p = 0.02) were independent risk factors for CMPA. On the other hand, exclusive breastfeeding (p = 0.001) and weaning food after six months (p = 0.03) were protective factors for CMPA. Gastrointestinal symptoms were the main manifestations of CMPA. The incidence of malnutrition, anemia, low total protein, and hypoalbuminemia was significantly higher in children with severe CMPA. In our locality, the history of parent’s food allergy, cesarean section, and the use of weaning food before four months of age were independent risk factors for CMPA. On the other hand, exclusive breastfeeding and weaning food after six months were protective factors for CMPA.