Objective To explore the effect of lncRNA HOXA-AS3 on cisplatin resistance in small cell lung cancer cells and its regulatory effect on miR-340-5p. Methods The expression levels of HOXA-AS3 and miR-340-5p in lung cancer tissues and adjacent tissues were measured by qRT-PCR. Small cell lung cancer cell line DMS114 was cultured in vitro and drug-resistant cell line DMS114 / DDP was established by increasing the concentration of cisplatin. si-NC, si- HOXA-AS3, si-HOXA-AS3, anti-miR-NC, si-HOXA-AS3 and anti-miR-340-5p were transfected into DMS114 / DDP cells. The expression levels of HOXA-AS3 and miR-340-5p in cells were measured by qRT-PCR. CCK-8 assays were used to measure cell survival rate and calculate the IC₅₀ value of cisplatin. Flow cytometry was used to assess the apoptosis rate. Dual luciferase reporter assays were used to analyze the targeting relationship between HOXA-AS3 and miR-340-5p. Results The expression level of HOXA-AS3 in lung cancer tissue was increased significantly (P<0.05) and that of miR-340-5p was decreased significantly (P<0.05). After treatment with various concentrations of cisplatin, the survival rates of DMS114 and DMS114 / DDP cells were decreased gradually (P<0. 05) and the IC₅₀ value of DMS114 / DDP cells was higher than that of DMS114 cells (P<0. 05). Compared with DMS114 cells, the expression level of HOXA-AS3 in DMS114 / DDP cells was increased significantly (P<0.05). Transfection with si-HOXA-AS3 significantly reduced cell viability (P<0.05) and increased the apoptosis rate (P<0.05). Dual luciferase reporter assays confirmed that HOXA-AS3 targeted and bound to miR-340-5p. Cotransfection of si-HOXA-AS3 and anti-miR-340-5p significantly increased cell viability ( P< 0.05) and reduced the apoptosis rate ( P< 0.05 ). Conclusions Interfering with the expression of HOXA-AS3 inhibits cell proliferation and promotes apoptosis, thereby enhancing the sensitivity of DMS114 / DDP cells to cisplatin. The mechanism of action may be related to upregulation of miR-340-5p expression.