<p>Partial hepatectomy (PH) triggers acute liver insufficiency and a tightly-orchestrated regenerative program. Here we show that artesunate (ART) markedly accelerates liver mass restoration in mice subjected to PH. ART elevated the liver index, normalized serum total protein and albumin, and curbed ALT/AST leakage. Histologically, ART attenuated hepatocellular necrosis and reduced lesion scores in a dose-dependent manner. Mechanistically, ART amplified Ki67-positive hepatocytes, suppressed apoptosis, and shifted cell-cycle distribution from G1 arrest toward G2/M progression. These regenerative effects were associated with enhanced mitophagy-related changes, as evidenced by increased TOM20/LC3B co-localization, elevated LC3-II/I ratio, increased PINK1 and Parkin expression, and reduced p62 accumulation. A chloroquine-based lysosomal inhibition assay further supported that ART enhanced mitophagy-associated flux. Docking analysis suggested a potential interaction between ART and AMPKα1/2, with docking energies of − 6.41 and − 6.45&#xa0;kcal mol^− 1 for PRKAA1 and PRKAA2, respectively. ART increased p-AMPKα1/2 and suppressed mTOR signaling, as further supported by reduced p-S6 expression. Pharmacological inhibition of AMPK with Compound C attenuated ART-induced PINK1/Parkin-associated mitophagy-related signaling, suppressed ART-enhanced hepatocyte proliferation, increased apoptosis, and partially reversed the ART-mediated reduction in p-S6 expression. Collectively, these findings suggest that ART promotes post-PH liver regeneration by activating AMPKα1/2-associated signaling and enhancing mitophagy-associated flux, positioning ART as a potential adjunct strategy for liver regeneration after hepatectomy.</p>