Introduction The management of pyogenic liver abscesses usually requires 4 weeks of antibiotic therapy. It is unknown if oral (PO) antibiotics are as effective as intravenous (IV) antibiotics for this indication. Objectives To compare 30‐, 60‐, and 90‐day readmission rates between patients with pyogenic liver abscesses receiving IV antibiotics for the duration of therapy and those who were transitioned to PO antibiotics after discharge from the hospital. Methods This retrospective study included patients with pyogenic liver abscesses who had undergone percutaneous drainage and received IV antibiotics while in the hospital. Patients were grouped based on receipt of either PO or IV antibiotics at discharge. Results The final cohort resulted in 99 patients, 48 in the PO group and 51 in the IV group. The most common organisms identified were Klebsiella sp, Escherichia coli, and Streptococcus sp. The most common antibiotic received at discharge in the IV group was ertapenem or ceftriaxone plus metronidazole. Patients in the PO group most commonly received levofloxacin plus metronidazole at discharge. Thirty‐day readmission occurred more frequently in the PO group (PO 39.6% vs IV 17.6%, p=0.03). The most common reasons for readmission were complications related to abscess or antibiotic. Univariate logistic regression for readmission identified PO antibiotics at discharge as an independent predictor of readmission at 30 days (odds ratio [OR] 3.1), 60 days (OR 3.9), and 90 days (OR 3.1). Conclusion Transition to PO antibiotics that consisted mostly of fluoroquinolones for patients with pyogenic liver abscesses was associated with a higher rate of 30‐day readmission compared with patients treated with IV antibiotics that consisted mostly of β‐lactams.