Preventive effects and corresponding molecular mechanisms of mugwort () extract and its flavonoid constituents on contrast-induced nephrotoxicity were explored in the present study. We treated cultured LLC-PK1 cells with iodixanol to induce contrast-induced nephrotoxicity, and found that extracts ameliorated the reduction in cellular viability following iodixanol treatment. The anti-apoptotic effect of extracts on contrast-induced nephrotoxicity was mediated by the inhibition of mitogen-activated protein kinase (MAPK) phosphorylation and the activation of caspases. The flavonoid compounds isolated from improved the viability of iodixanol-treated cells against contrast-induced nephrotoxicity. Seven compounds (, , , , , , and ) from 19 flavonoids exerted a significant protective effect. Based on the in silico oral-bioavailability and drug-likeness assessment, which evaluate the drug potential of these compounds, compound (artemetin) showed the highest oral bioavailability (49.55%) and drug-likeness (0.48) values. We further investigated the compound⁻target⁻disease network of compound , and proliferator-activated receptor gamma (PPAR-γ) emerged as a predicted key marker for the treatment of contrast-induced nephrotoxicity. Consequently, compound was the preferred candidate, and its protective effect was mediated by inhibiting the contrast-induced inflammatory response through activation of PPAR-γ and inhibition of MAPK phosphorylation and activation of caspases.