Antibiotic resistance poses a global concern due to its impact on treatment efficacy and public health. This study delves into antibiotic prescription patterns and emphasizes the imperative need for Antimicrobial Stewardship Programs (ASPs) in tertiary care hospitals. Analyzing factors contributing to resistance, such as improper usage, underscores the urgency of addressing this issue. Methods: A retrospective analysis conducted in Erode Tertiary Care Hospitals over six months scrutinized antibiotic prescriptions for in-patients in the General Medicine department. Data collection involved discharge summaries, extracting information on prescriptions, diagnoses, demographics, and antibiotic details. Culture sensitivity reports and drug interactions were assessed, aligning with WHO's antibiotic categorization (AWaRe). Results: Among 325 participants, predominant antibiotic classes included Cephalosporins and Fluoroquinolones. Ciprofloxacin, Metronidazole, and Ceftriaxone emerged as the most frequently prescribed. The majority received therapy for 3–5 days, primarily through injections. Alarmingly, culture sensitivity testing was minimal (1.23%). Comorbidities were prevalent (26.46%), with 37.20% of these prescriptions indicating potential drug-drug interactions. Conclusion(s): The study highlights prevalent broad-spectrum antibiotic usage, minimal culture sensitivity testing, and significant potential drug interactions in comorbid patients. Urgent implementation of ASPs in tertiary care hospitals remains crucial to optimize antibiotic use, promote judicious prescribing, and enhance patient-specific treatment strategies. This step is essential for better outcomes and effectively combating antibiotic resistance.