Total knee arthroplasty (TKA) is the most common and cost-effective treatment for older adults with long-standing osteoarthritis. During TKA, muscle cells suffer from prolonged oxygen deficiency, which leads to altered cell metabolism that reduces the energy demand and maintains cell homeostasis before blood flow is restored. This study focused on the role of the lncRNA muscleblind-like 1 antisense RNA 1 (MBNL1-AS1) in protecting sevoflurane-pretreated mice against ischemia-reperfusion (I/R) injury after TKA, as well as the elucidation of the potential associated mechanism. Identification of differentially expressed lncRNAs was performed using the microarray dataset GSE21164, which was extracted from the GEO database. Target genes of the lncRNA were determined using Multi-Experiment Matrix (MEM), a dual-luciferase reporter gene assay, and KEGG enrichment analyses. The results showed that MBNL1-AS1 was overexpressed in skeletal muscle cells in mice, while KCNMA1, which was enriched in the cGMP-PKG signaling pathway, was negatively regulated by MBNL1-AS1. Furthermore, I/R mice displayed serious inflammatory reactions. Down-regulation of MBNL1-AS1 increased the expression of KCNMA1, PKGII, VASP, VEGF, Bcl-2, Cyclin D1, Cyclin D3, and Cdc 42 but decreased the expression of Bax, cleaved caspase-3, and cleaved PARP. Furthermore, upon MBNL1-AS1 upregulation, the rate of cell apoptosis increased while the rate of cell proliferation decreased. Our data suggested that down-regulated lncRNA MBNL1-AS1 might promote the proliferation and inhibit the apoptosis of skeletal muscle cells by upregulating KCNMA1 expression via activation of the cGMP-PKG signaling pathway, thus protecting sevoflurane-pretreated mice against I/R injury after TKA.