This study was conducted to determine the alterations of inflammatory cytokines, energy metabolic regulators, and muscle fiber type in the LM of the piglets postweaning. Crossbred piglets (Landrace x Large White) weaned at 14 d age were randomly selected from 8 litters and slaughtered at 0 (W0), 1 (W1), 3 (W3), 5 (W5), or 7 (W7) days postweaning. The glycogen content, free glucose concentration, and enzyme activities, including ATPase (Na+/K+, Ca2+/Mg2+), creatine kinase, and lactic dehydrogenase (LDH), were detected in the skeletal muscle tissue. Concentrations of proinflammatory cytokines, including IL-1 beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha), and anti-inflammatory cytokines, including IL-10 and transforming growth factor-beta 1 (TGF-beta 1), were measured in serum. The mRNA abundance of the above cytokines, energy metabolic regulators, and muscle fiber type related genes were determined via real-time quantitative PCR analysis. The adenosine monophosphate-activated protein kinase alpha (AMPK alpha) signaling was measured by Western blot analysis. Our results showed ATPase activities were lower on W7 d but LDH activity was higher on W3 d after weaning (P < 0.05). Serum TNF-alpha concentration was markedly increased on W1 d, then returned to the value of preweaning (P < 0.05), and almost all the values of inflammatory cytokines were reduced to a low point on W5 d after weaning. Additionally, the IL-6 mRNA abundance was upregulated during W3 to W7 d, but cytokine TNF-alpha was upregulated just on W7 d (P < 0.05). The mRNA abundance of AMPKa and uncoupling protein (UCP) 3 were both higher on W1 and W3 d, and UCP2 was higher on W7 d postweaning (P < 0.05). Myosin heavy chain (MyHC) I and MyHC IIx-type fibers were enhanced on W1 d, then returned to the value of preweaning, and the MyHC IIb-type fiber was significantly increased on W5 and W7 d (P < 0.05). Meanwhile, the value of P-AMPK alpha/T-AMPK alpha increased on W3 d postweaning (P < 0.05) compared with that on W0 d. These results indicate that weaning stress induced inflammation in skeletal muscle tissue during at least 7 d postweaning. It upregulated the expression of proinflammatory cytokines, which then stimulated the AMPK alpha and UCP involved in energy metabolism events, accompanied by significant alterations in muscle fiber type.