<p>Non-steroidal anti-inflammatory agents are widely used for their analgesic, anti-inflammatory, and antipyretic effects, and a prominent representative of the drug family, diclofenac has recently been proposed for cancer therapy. However, overdose of diclofenac has also been reported to cause liver toxicity, whereas olaparib, a widely used antineoplastic poly (ADP-ribose) polymerase inhibitor, is known for its mitochondria-mediated cytoprotective properties. In this study, we used HepG2 human hepatocellular carcinoma cells, which retain various characteristics of hepatocytes, to study the interaction between these two drugs. We found that diclofenac caused a 20–50% decrease in the viability and invasive growth of the cells, which olaparib ameliorated by approximately 50%. Additionally, olaparib reversed diclofenac-induced mitochondrial depolarization as demonstrated by JC-1 fluorescence microscopy and flow cytometry. Furthermore, although not possessing significant free-radical scavenging properties according to the cell-free Fenton reaction system, olaparib also mitigated diclofenac-induced reactive oxygen species production and apoptosis-inducing factor-mediated parthanatos. Using the Seahorse cellular respirometer, we showed that diclofenac shifted the energy production of HepG2 cells toward oxidative phosphorylation by approximately 40%, whereas olaparib reversed this effect, suggesting that the two drugs may have opposite effects on the metabolic reprogramming of cancer cells. Therefore, further studies are needed before considering their combined use for oncological applications. Additionally, we demonstrated that complex I inhibition and preservation of cellular NAD⁺ pool are unlikely to be involved among the mechanisms of olaparib’s protective effect.</p>