Objective <p>The primary aim of the study was to evaluate the incidence of congenital anomalies (CAs) and their association with maternal and environmental factors among live-born infants in Isfahan Province, Iran.</p> Methods <p>This cross-sectional study was conducted from September 2023, to May 2024. A total of 2555 women of reproductive age (15–55 years) who had at least one live birth, residing in Isfahan Province (central Iran), were selected using multistage random sampling from the internet-based health event database of the Ministry of Health, known as SIB. These women were invited to complete an online validated questionnaire, either during a telephone interview or in person. Univariate and multivariable logistic regression analyses were conducted to investigate the relationships between CAs and factors such as maternal age, consanguinity, parity, socioeconomic status, lifestyle, and nutritional characteristics.</p> Results <p>A total, 34 live births were classified as CAs, representing 1.33% (95% confidence interval: 0.92–1.85), which is lower than the national estimate of 1.8% and the global estimate of 2–3% for major congenital anomalies, as reported in the World Health Organization’s fact sheet on congenital anomalies. The significant predictors of congenital anomalies were advanced maternal age (odds ratio [OR] = 1.05, 95% CI: 1.00–1.09, <i>p</i> = 0.001), first-degree consanguineous marriage (OR = 5.46, 95% CI: 2.16–9.20, <i>p</i> &lt; 0.001), and higher parity (OR = 6.80, 95% CI:1.85–24.98 for four or more pregnancies, <i>p</i> = 0.002).</p> Conclusion <p>These findings highlight the importance of targeted interventions, including expanded genetic counseling, improved prenatal screening for high-risk groups, and the creation of a national CA registry.</p>