Background: This study aimed to evaluate systemic antibiotics' prescription patterns and effectiveness in managing acute periapical pathologies, focusing on factors influencing their use and associated treatment outcomes. Methods: A cross-sectional observational study was conducted at Rehman College of Dentistry, Peshawar, from January 2023 to January 2024. A total of 120 patients with acute periapical infections were included. Data were collected using structured questionnaires and clinical records, covering demographic details, clinical presentations, antibiotics prescribed, and treatment outcomes. Statistical analyses were performed to identify significant associations, with a p-value of <0.05 considered statistically significant. Results: Most participants were aged 31–50 (41.7%), with males comprising 58.3% of the sample. The most frequent primary diagnosis was acute abscess, while the remaining participants were diagnosed with periapical granuloma. Amoxicillin was the most commonly prescribed antibiotic (58.3%), followed by metronidazole (25.0%) and clindamycin (16.7%). Antibiotics were prescribed primarily for systemic symptoms, but 25.0% of prescriptions were deemed inappropriate. Most patients (58.3%) experienced symptom resolution within three days, with high patient satisfaction (66.7%). Practitioner experience and guideline adherence were significant factors influencing appropriate antibiotic use, while patient compliance was a key determinant of successful outcomes. Conclusion: Systemic antibiotics are essential in managing acute periapical infections, but inappropriate prescriptions remain a concern. Enhancing adherence to clinical guidelines and educating practitioners and patients on rational antibiotic use are necessary to optimise outcomes and prevent antimicrobial resistance.