Background <p>Neonatal appendicitis (NA) is a rare but potentially fatal condition with diagnostic challenges and limited management evidence. This study evaluates the efficacy of nonoperative treatment compared to surgical intervention.</p> Methods <p>A retrospective study included infants ≤ 28 days with clinically and sonographically confirmed NA treated at four institutions between January 2010 and May 2022. The nonoperative group received antibiotics and supportive care, compared to a control group of 34 surgically treated neonates. The primary outcome was nonoperative treatment failure (death or delayed appendectomy), while secondary outcomes included severe infectious complications, hospital stay, costs, and readmission.</p> Results <p>Twenty-eight neonates (median age 11 days; 35.7% female) received nonoperative therapy. The failure rate was 25%, with 3 deaths (10.7%) and 5 delayed appendectomies (17.9%). Severe infectious complications occurred in 28.6% of cases, higher than the surgical group, but not statistically significant (<i>P</i> = 0.10). Hospital costs were significantly lower for the nonoperative group (<i>P</i> &lt; 0.05). No recurrence was observed over 6.2 years of follow-up.</p> Conclusions <p>Nonoperative treatment of NA was associated with a high failure rate, mortality, and complication rate, despite lower costs. Given limited power for several comparisons, our findings suggest early surgical intervention may be preferable.</p>