Solamargine (SM) has been shown to have anti-cancer properties. However, the underlying mechanism involved remains undetermined. We showed that SM inhibited the growth of non-small cell lung cancer (NSCLC) cells, which was enhanced in cells with silencing of long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR), while it overcame by overexpression of HOTAIR. In addition, SM increased the expression of miR-214-3p and inhibited 3-phosphoinositide-dependent protein kinase-1 (PDPK1) gene expression, which was strengthened by miR-214-3p mimics. Intriguingly, HOTAIR could directly bind to miR-214-3p and sequestered miR-214-3p from the target gene PDPK1. Intriguingly, overexpression of PDPK1 overcame the effects of SM on miR-214-3p expressions and neutralized the SM-inhibited cell growth. Similar results were observed in vivo. In summary, our results showed that SM-inhibited NSCLC cell growth through the reciprocal interaction between HOTAIR and miR-214-3p, which ultimately suppressed PDPK1 gene expression. HOTAIR effectively acted as a competing endogenous RNA (ceRNA) to stimulate the expression of target gene PDPK1. These complex interactions and feedback mechanisms contribute to the overall effect of SM. This unveils a novel molecular mechanism underlying the anti-cancer effect of SM in human lung cancer.