In recent years, Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) have surfaced as a novel class of pollutants due to their incomplete degradation in wastewater treatment plants and their inherent ability to promote physiological predicaments in humans even at low doses. The occurrence of the most common NSAIDs (diclofenac, ibuprofen, naproxen, and ketoprofen) in river water, groundwater, finished water samples, WWTPs, and hospital wastewater effluents along with their toxicity effects were reviewed. The typical concentrations of NSAIDs in natural waters were mostly below 1 μg/L, the rivers receiving untreated wastewater discharge have often showed higher concentrations, highlighting the importance of effective wastewater treatment. The critical analysis of potential, pathways and mechanisms of microbial degradation of NSAIDs were also done. Although studies on algal and fungal strains were limited, several bacterial strains were known to degrade NSAIDs. This microbial ability is attributed to hydroxylation by cytochrome P450 because of the decrease in drug concentrations in fungal cultures of Phanerochaete sordida YK-624 on incubation with 1-aminobenzotriazole. Moreover, processes like decarboxylation, dehydrogenation, dechlorination, subsequent oxidation, demethylation, etc. also constitute the degradation pathways. A wide array of enzymes like dehydrogenase, oxidoreductase, dioxygenase, monooxygenase, decarboxylase, and many more are upregulated during the degradation process, which indicates the possibility of their involvement in microbial degradation. Specific hindrances in upscaling the process along with analytical research needs were also identified, and novel investigative approaches for future monitoring studies are proposed.