<p>Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for pyrexia, dysmenorrhea, operative pain, and arthritic pain due to their analgesic, antipyretic, and anti-inflammatory properties. A recent investigation indicates that NSAIDs may possess prophylactic properties against mammary tumor. Their anti-neoplastic potential is associated with chronic inflammation in the development of tumors. NSAIDs exhibit anti-breast cancer activity potentially by targeting COX-2, an enzyme overexpressed in many solid tumors, or by altering several pathways, including NF-κB, JAK-STAT, MAPK, PI3K/Akt, mTOR, Wnt/β-catenin, and CREB, involved in cell cycle regulation, development, and progression of the tumor. In addition, NSAIDs can alter the expression of pro- and anti-apoptotic proteins that regulate cell survival. Researchers have developed a variety of derivatives, such as ester, phospho-ester, thioester, amide, hydrazide, metal complexes, and salt derivatives, to improve the anticancer activity and selectivity of NSAIDs. These novel derivatives exhibited excellent outcomes in preclinical investigations against various breast cancer cell lines, highlighting enhanced cytotoxicity and bioavailability and minimizing adverse effects as compared to standard NSAIDs. This review emphasizes the anti-breast cancer potential of NSAIDs and their novel derivatives by targeting novel molecular targets in mammary tumorigenesis, focusing on both COX-dependent and independent pathways. Investigating these NSAID derivatives offers an optimistic approach to the development of safer, more efficient anticancer agents for the treatment of breast cancer.</p><p></p>