Post-operative pain is an unpleasant experience for patients after undergoing surgery. Anesthesia practice often relies on the use of opioids before and after surgery to manage post-operative pain. However, surgery involving high doses of opioids can increase the risk of post-operative complications. One of the drugs that is often used as an alternative to treat post-surgical pain is ketamine. A systematic review of randomized controlled trials (RCTs) was conducted electronically using Google Scholar and PubMed. This review aimed to compare the analgesic effect of ketamine vs fentanyl to outcomes (pain intensity, pain presence, time to onset of analgesia, and any adverse events). The study utilized standard PICO (population, intervention, comparator, and outcomes) for systematic reviews. There was a significant difference between systolic and diastolic blood pressure in patients induced with ketamine and patients induced with fentanyl at 3 and 5 minutes. The average systolic and diastolic blood pressure values of patients induced with fentanyl were lower than those of patients induced with ketamine. The group of patients induced with fentanyl could achieve lower systolic and diastolic blood pressure than patients induced with ketamine. The ketamine group had a better total QoR-40 score than the fentanyl group; this is often due to the typical side effects of fentanyl. Overall, the fentanyl group had a higher Post-Sedation Symptom Inventory (PSSI) score than the ketamine group. The ketamine group had a higher pain value according to the Hannallah scale and Pediatric Anesthesia Emergence Delirium (PAED) than the fentanyl group, but it was not significantly different in pediatrics. In conclusion, ketamine provides a safe and effective alternative to opioids (fentanyl) for analgesia during surgical procedures if lower hypotensive side effects and a better level of post-operative comfort are desired in adult patients.