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The current study proposes the in vitro and in silico anticancer evaluation of clove (Syzygium aromaticum L.) essential oil (CEO). The steam hydrodistillation method used yielded 10.7% (wt) CEO. GC-MS analysis revealed that the obtained oil is rich in eugenol (75%), β-caryophyllene (20%), and α- caryophyllene (2.8%) and also contains several other minor components accounting for approximately 1.5%. The DPPH-based scavenging antioxidant activity was assessed for the obtained CEO, exhibiting an IC50 value of 158 μg/mL. The cytotoxic effects of CEO, its major component eugenol, and CEO solubilized with Tween-20 and PEG-400 were tested against both noncancerous HaCaT cells and HT-29 human colorectal adenocarcinoma, RPMI-7951 melanoma, A431 skin carcinoma, and NCI-H460 non-small lung cancer cells, using the Alamar Blue and LDH assay after 48 h treatment. The Tween-20 and PEG-400 CEO formulations, at 200 μg/mL, recorded the highest cytotoxic and selective effects against RPMI-7951 (72.75% and 71.56%), HT-29 (71.51% and 45.43%), and A431 cells (61.62% and 59.65%). Furthermore, CEO disrupted mitochondrial function and uncoupled oxidative phosphorylation. This effect was more potent for the CEO against the RPMI-7951 and HT-29 cells, whereas for the other two tested cell lines, a more potent inhibition of mitochondrial function was attributed to eugenol. The present study is the first to specifically investigate the effects of CEO and Tween-20 and PEG-400 CEO formulations on the mitochondrial function of RPMI-7951, HT-29, A431, and NCI-H460 cancer cell lines using high-resolution respirometry, providing novel insights into their impact on mitochondrial respiration and bioenergetics in cancer cells. The results obtained may explain the increased ROS production observed in cancer cell lines treated with eugenol and CEO. Molecular docking identified potential protein targets, related to the CEO anticancer activity, in the form of PI3Kα, where the highest active theoretical inhibitor was calamenene (−7.5 kcal/mol). Docking results also showed that calamenene was the overall most active theoretical inhibitor for all docked proteins and indicated a potential presence of synergistic effects among all CEO constituents. [ABSTRACT FROM AUTHOR]