The present study aimed to explore how histone deacetylases 3 (HDAC3) regulated the resistance to cisplatin by inhibiting the transcription of lncRNA-LOC101928316 (LOC101928316) in gastric cancer (GC). We revealed that HDAC3 expression in cisplatin-resistant cell lines was significantly higher than that of GC parental cell lines. Besides, knockdown of HDAC3 inhibited the cell activity, cell invasion, and migration but promoted the apoptosis of GC cisplatin-resistant cell lines. To our surprise, silencing HDAC3 inhibited the transcription of LOC101928316 by promoting the level of acetylation of H3K4 on the LOC101928316 promoter, thus promoting the LOC101 expression in GC cisplatin-resistant cell lines. Together, the overexpression of HDAC3 mediated LOC101928316 to promote GC resistance to cisplatin by activating the PI3K-Akt-mTOR pathway. Therefore, HDAC3 may serve as a potential target of cisplatin resistance in GC.