Diclofenac sodium (Dc) was found to possess antibacterial activity against both drug-sensitive and drug-resistant clinical isolates of Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Mycobacterium spp., in addition to its potent anti-inflammatory activity. The time-kill curve study indicates that this non-steroidal drug exhibits bactericidal activity against Listeria, E. coli, and M. tuberculosis. The antibacterial activity of Dc comes, in part, from its ability to inhibit the DNA synthesis of E. coli and L. monocytogenes. Dc could protect murine listeriosis, salmonellosis, and tuberculosis at doses ranged within its maximum recommended human or non-toxic ex-vivo dose. Dc possesses anti-plasmid activity and acts as a 'helper compound' in synergistic combination with streptomycin against E. coli and Mycobacterium or gentamicin against Listeria. This review focuses on the possible use of Dc, a non-antibiotic helper compound, in infections and inflammatory conditions, rationalized on the basis of the activities of the compounds.