Purpose <p>Acute pyelonephritis is a common diagnosis in ambulatory settings. The objective of this systematic review was to assess whether oral antibiotic treatment is non-inferior to a single dose of IV antibiotics followed by oral relay in terms of efficacy and complications in adult patients presenting to the emergency department (ED) with acute pyelonephritis.</p> Methods <p>The protocol was registered to PROSPERO (CRD42024503968). Five databases (MEDLINE, Embase, CINAHL, CENTRAL, and Web of Science) and grey literature were searched for randomized controlled trials (RCT) and observational studies comparing both treatment strategies. Two reviewers independently performed study selection, data extraction, and quality assessment (RoB 2 and ROBINS-I). The primary outcomes were clinical and microbiological cure. A structured reporting of the effects for each study was conducted since meta-analysis was not appropriate.</p> Results <p>The search yielded 2,956 records, with 909 duplicates. After screening, 40 full texts were reviewed, and 3 studies were included. Two studies (1 RCT, 1 non-randomized) reported on the primary outcomes, without assessing non-inferiority. These did not report a difference in clinical and microbiological cure between treatment strategies at end of follow-up. The risk of bias was moderate to serious/high.</p> Conclusion <p>This review identified few studies comparing oral-only to single-dose IV followed by oral antibiotics for acute pyelonephritis in adults. Non-inferiority of oral-only treatment could not be established, as none of the included studies were designed for this purpose. Clarifying the comparative effectiveness of these two approaches is essential to further optimize the management of acute pyelonephritis.</p>