Background: Although it has been suggested that papillary morphology and periampullary diverticulum (PAD) may affect the outcomes of endoscopic retrograde cholangiopancreatography (ERCP), the independent effects of these factors have not been clearly established. In this study, we aimed to evaluate the association of papillary morphology and PAD with ERCP success, procedural difficulty, and post-ERCP complications. Methods: Records of 1046 ERCP procedures performed at a single center were retrospectively reviewed. The primary analysis included 693 patients with native papillae and no prior sphincterotomy. Papilla morphology was available for 381 patients and periampullary diverticulum (PAD) status for 633. Outcomes included cannulation success, difficult cannulation, cannulation time, number of cannulation attempts, post-ERCP complications, and length of hospital stay. Multivariable Firth penalized logistic regression was used to evaluate independent associations with difficult cannulation, overall complications, cannulation failure, and post-ERCP pancreatitis (PEP), adjusting for papilla morphology, PAD status, age, sex, American Society of Anesthesiologists (ASA) physical status class, and Charlson Comorbidity Index (CCI). Results: Regular papilla morphology, compared with the pooled group of atypical papilla morphologies (Small, Bulging, Ridged), was associated with significantly higher cannulation success (97.4% vs. 91.2%; p = 0.012), shorter cannulation time (median 3.0 vs. 4.0 min; p = 0.009), fewer cannulation attempts (p = 0.007), and shorter hospital stay (median 5.0 vs. 6.0 days; p = 0.013). The presence of a PAD was not significantly associated with any procedural outcome or complication (all p > 0.05). CCI was independently associated with cannulation failure (adjusted OR 1.40 per one-point increase; 95% CI 1.03–1.91; p = 0.031) and was the only factor reaching statistical significance across the four multivariable models. The multivariable model showed modest discrimination for difficult cannulation (area under the receiver operating characteristic curve [AUC] = 0.596; 95% CI 0.515–0.675). Conclusions: Atypical papillary morphology was associated with lower cannulation success, longer cannulation time, and more cannulation attempts in univariable analyses; however, neither papillary morphology nor periampullary diverticulum was independently associated with ERCP outcomes. Among the variables evaluated, higher CCI was the only factor independently associated with cannulation failure; however, this finding should be interpreted cautiously given the small number of failure events.