Semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is increasingly prescribed for the management of type 2 diabetes mellitus and obesity owing to its proven efficacy in glycogenic control and weight reduction. However, with expanding use, a broader spectrum of adverse drug reactions (ADRs)—ranging from common gastrointestinal intolerance to rare but clinically significant complications—has been increasingly recognized, underscoring the need for continued real-world pharmacovigilance. Objective: To describe a case series of semaglutide-associated ADRs reported from a tertiary care centre in India, highlighting the variability in clinical presentation, the role of uniform baseline investigations, and the importance of comprehensive medication history in causality assessment. Methods: Five patients receiving semaglutide for type 2 diabetes mellitus (n = 3) or obesity (n = 2) developed clinically significant ADRs. All cases underwent uniform baseline and follow-up investigations, including complete blood count, liver and renal function tests, serum electrolytes, and glycogenic parameters (HbA1c/fasting plasma glucose). Detailed drug histories, co morbidities, and concomitant medications were systematically reviewed. Causality assessment was performed using the WHO–UMC criteria. Results: The documented ADRs comprised generalized pruritus (n = 1), severe nausea and vomiting (n = 2), acute kidney injury (n = 1), and gastro paresis-like symptoms (n = 1). All reactions demonstrated a clear temporal relationship with semaglutide initiation or dose escalation and were categorized as probable on WHO–UMC causality assessment. Alternative aetiologies, including concomitant medications and underlying comorbidities, were reasonably excluded. Clinical improvement and complete resolution of symptoms were observed in all patients following discontinuation and appropriate supportive management. Conclusion:  Although semaglutide is an effective and widely used therapeutic agent, this case series highlights the occurrence of clinically relevant ADRs in routine clinical practice within an Indian tertiary care setting. The findings reinforce the importance of uniform baseline evaluation, cautious dose titration, meticulous medication history, and proactive pharma covigilance reporting through the Pharma covigilance Programme of India (PvPI) to enhance patient safety and sustain therapeutic confidence.