Meniscus injuries are challenging to treat due to the tissue heterogeneity and limited treatment efficacy. Understanding meniscus cell migration, crucial for healing, remains incomplete, especially its zonal dependency. This study explores how epigenetic mechanisms affect meniscus cell migration under inflammation, focusing on healing implications. Distinct histone modifications and chromatin dynamics between inner and outer cells were observed during migration, emphasizing the need to consider these differences in repair strategies. Furthermore, tumor necrosis factor alpha (TNF-α), a proinflammatory cytokine, slows inner meniscus cell migration, while outer cells remain unaffected, indicating a zonal response. Interestingly, TNF-α differentially alters histone modifications, particularly H3K27me3, between the cell types. Transcriptome analysis showed significant gene expression changes with inner cells more affected than outer cells. Gene cluster analysis revealed different responses in chromatin remodeling, extracellular matrix assembly, and wound healing between zones. We further identified potential therapeutic targets by using epigenetic drugs, GSKJ4 (a histone demethylase inhibitor) and C646 (a histone acetyltransferase inhibitor), which restored inner meniscus cell migration under inflammatory conditions, highlighting their potential in treating meniscus tears. This highlights their potential utility in treating meniscus tear injuries. Overall, our findings elucidate the intricate interplay between epigenetic mechanisms and meniscus cell migration, along with its meniscus zonal dependency. This study provides insight into potential targets for enhancing meniscus repair and regeneration, which may lead to improved clinical outcomes for patients with meniscus injuries and osteoarthritis.