Naproxen is a medication classified as a non-steroidal anti-inflammatory medicine (NSAID) utilized for its anti-inflammatory properties. The principal functional group in naproxen is the carboxyl group, prompting numerous researchers to modify this group to synthesize novel derivatives of naproxen and investigate their pharmacological efficacy, with the aim of discovering more effective molecules than naproxen. This review examines the methodologies for synthesizing derivatives, emphasizing notable molecules with unique biological activity and the key techniques employed in these investigations. Modification of naproxen to include triazole 5n has been found to enhance the efficacy of the derivative and constitute a potential treatment for prostate cancer. The presence of pyrazole and pyrazoline derivatives 9c and 12f enhances the anti-inflammatory and anti-proliferative activity of the derivative. Research has also found that modifying the carboxyl group of naproxen to derivatives containing heterogeneous sulfur rings, such as thiazole and thiadiazole 14a and 22q, whether as single or fused rings, enhances its anti-inflammatory and analgesic activity. Amines and amino acids 26a, 26b, 29b, 32b, and 33b have also been observed to enhance its anti-inflammatory and analgesic activity. These compounds exhibited high oral absorption and were not carcinogenic or toxic in rodent studies, showing safety and minimal ulceration. The most prominent derivatives that inhibit the COX-2 enzyme are hydrazone derivatives that contain the functional group (-NH-N=CH-), and the substituted m-chlorophenyl 35c emerged as the most inhibitory derivative.