Diospyros lotus, also known as date-plum, belongs to theEbenaceaefamily and is mostly recognized as a rootstock forD.kaki. Similar classes of naphthoquinones inD.lotusare investigated against cancer and inflammation and have antimicrobial, sedative, and analgesic properties. Six chemical constituents (1-6) were isolated fromDiospyros lotusand tested for anti-inflammatory effects at the dose of 2.5 and 5 mg/kg, i.p., using carrageenan (1%, 0.05 ml)-induced paw edema. The maximum protection against carrageenan-induced edema was observed for compounds 1 and 2. Both studied compounds demonstrated significant anti-inflammatory effect after the 3^rdhour of posttreatment. The maximum anti-inflammatory effect of compound 1 was 85.96%, while that of compound 2 was 81.44%, followed by compounds 5 and 6, which exhibited 80.11% and 82.45% effect, respectively. Similarly, histamine-induced inflammation was significantly antagonized by 1, 2, 5, and 6 with 87.99%,82.18±1.8,80.40±1.59, and 77.44% effects, respectively, at 5 mg/kg after the 2^ndhour of posttreatment. The rest of the tested compounds did not show any significant effect as compared to the negative control. Interestingly, no toxicity was observed at higher doses. Moreover, the extracted compounds showed remarkable antibacterial activity against the Gram-positive bacteria and no effect against the Gram-negative bacteria. Docking studies on target cyclooxygenases showed that all the compounds established interactions with the key amino acid residues present in the additional pocket of COX-2. Hence, these compounds may act as selective COX-2 inhibitors. In conclusion, the findings of the current study suggest that the roots ofDiospyros lotusmay contain some anti-inflammatory and antibacterial agents with minimal toxicological effects and accordingly this plant product is recommended for further investigations.