Oxycodone and fentanyl are potent opioid painkillers used to manage moderate to severe pain but differ significantly in strength and risk. Oxycodone is a semi-synthetic opioid commonly prescribed in pill form for chronic pain. Fentanyl, a fully synthetic opioid, is up to 50–100 times more potent than morphine and often used for severe or surgical pain. While both drugs can provide effective relief, fentanyl’s extreme potency increases the risk of overdose, especially when misused or mixed with other substances. Understanding their differences is crucial for safe medical use and for addressing the growing opioid misuse and overdose crisis.