This study aimed to investigate whether physcion 8-O-β-glucopyranoside (PG) exerted anti-tumor effects in endometrial cancer cells via regulating the long non-coding RNA lnc-SLC4A1-1. The anti-tumor effects of PG on endometrial cancer by evaluating Ishikawa cell growth and metastasis, and the expression of lnc-SLC4A1-1 was determined after PG treatment. Subsequently, the role and regulatory mechanism of lnc-SLC4A1-1 dysregulation in PG-treated endometrial cancer cells were explored. PG treatment resulted in dramatical depression of cell viability, remarkable promotion of cell apoptosis and dramatic suppression of migration and invasion in Ishikawa cells in a dose-dependent way. Moreover, PG decreased the level of lnc-SLC4A1-1, and high levels of lnc-SLC4A1-1 reversed the effects of PG on Ishikawa cells. Furthermore, lnc-SLC4A1-1 was transcriptionally activated by H3K27ac and interacted with NF-κB p65 in Ishikawa cells. PG treatment depressed the NF-κB signal in Ishikawa cells, which were significantly reversed after overexpression of lnc-SLC4A1-1. Our results indicate that PG exerts anti-tumor activity in endometrial cancer cells. Lnc-SLC4A1-1/H3K27ac/NF-κB pathway may be a possible mechanism to mediate the anti-tumor effects of PG, which provide a promising targeted strategy for treatment of endometrial cancer.