Background: Effective pain management remains a key clinical priority across a wide range of acute conditions. The combination of aceclofenac, paracetamol, and serratiopeptidase is commonly prescribed for its synergistic analgesic and anti-inflammatory effects. However, real-world evidence supporting its effectiveness and safety is limited. Objective: To evaluate the effectiveness and safety of aceclofenac in combination with paracetamol and serratiopeptidase in routine clinical practice. Methods: This multicenter, retrospective, real-world study analyzed data from 2,543 patients treated for various painful conditions. Demographic details, indications, duration of illness, clinical outcomes, and adverse events were assessed. Pain intensity was evaluated in a subset of patients (n = 879) using categorical scales (mild, moderate, severe). Results: The mean age of patients was 43.25 ± 12.18 years, with a male predominance (70.1%). The most common indication was injury/trauma (54.2%), followed by post-operative pain (31.1%), while other indications included dental pain (4.9%), generalized pain (4.6%), joint pain (3.4%) and low back pain (2.5%). The mean duration of illness prior to treatment was 7.2 ± 5.3 days. In the subset analysis, A marked improvement in pain intensity was observed, with the proportion of patients achieving complete pain resolution increasing to 79%, while moderate and severe pain decreased to 5% and 2%, respectively, indicating significant clinical effectiveness. A total of adverse events were infrequent and mild, with nausea (1.8%) being the most commonly reported, followed by abdominal pain (0.7%), gastritis (0.6%), and vomiting, heartburn, and diarrhea (0.4% each). Conclusion: The combination of aceclofenac, paracetamol, and serratiopeptidase demonstrated effective pain relief with a favorable safety profile in real-world clinical settings. These findings support its use as a reliable therapeutic option for the management of acute pain conditions.