Background Acute pancreatitis (AP) caused by gallstones has an increased rate of incidence in young women in the 2 years postpartum. Middle-aged women with longer periods of breastfeeding have less hospitalization for gallbladder disease. Aim To investigate whether breastfeeding or other variables may be associated with AP. Methods We conducted a population-based case–control study among all Sicilian women of childbearing age, and we identified all women who delivered (2013–2016) and had AP within 2 years postpartum. We reviewed their medical records, and for each case we matched four women of the same age (± 5 years), without AP. Univariate and multivariate logistic regression was used to estimate the odds ratios (OR) with their confidence intervals (CI) to assess associations between AP and clinical determinants. Results In the 74 women with AP and 298 controls at univariate analysis, > 6 months oral contraception history ( p  < 0.01; OR 3.30; 95% CI 1.33–8.16), previous biliary disease ( p  < 0.001; OR 5.90; 95% CI 1.98–17.57) and smoking ( p  = 0.035; OR 2.04; 95% CI 1.04–4.0) were predictors of AP; amenorrhea ≥ 3 months ( p  < 0.001; OR 0.34; 95% CI 0.19–0.59) and breastfeeding ≥ 3 months ( p  < 0.001; OR 0.07; 95% CI 0.03–0.14) were protective. At multivariate analysis, previous biliary disease ( p  = 0.011; OR 5.49; 95% CI 1.48–20.38) and breastfeeding ≥ 3 months ( p  < 0.001; OR 0.06; CI 95% 0.03–0.14) were associated with AP. Conclusions Women who breastfeed for at least 3 months and do not have a history of biliary disorders have reduced risk of developing AP in the 2 years after delivery.