Kidney stones typically present as renal colic in emergency departments (EDs), where patients experience severe pain and often require parenteral therapy for symptom management. The economic burden associated with managing kidney stones exceeds USD 5 billion annually in the US and accounts for more than a million visits to EDs each year. There is clear evidence emphasizing the need for innovative and alternative pain control options for patients with renal colic. Recent randomized controlled trials suggest that intranasal (IN) and intravenous (IV) ketamine are as effective as parenteral NSAIDs and opioids in treating renal colic. However, the limited studies available show inconsistent results regarding the analgesic effects of ketamine. In this study, we reviewed the mechanism of action of ketamine for kidney stones, its efficacy in treating acute renal colic, and the potential adverse side effects of ketamine treatment. A population, intervention, comparison, and outcome (PICO)-related question was formulated to guide our research inquiry: “What are the effects of IV or IN ketamine, as a single agent or as an adjuvant (I), in adult patients diagnosed with acute renal colic (P) on pain scale scores and adverse side effects (O) compared to NSAIDs and/or opioids (C)?”