Globally, lung cancer is known as a major cause of cancer-associated death and non-small-cell lung cancer (NSCLC) accounts for majority of all cases. Growing evidence has emerged that long non-coding RNAs (lncRNAs) act as vital regulatory molecules in various malignancies. Nevertheless, the function of SLCO4A1 antisense RNA 1(SLCO4A1-AS1) in NSCLC is vague. This study intended to investigate the biological role and probable regulatory mechanism of SLCO4A1-AS1 in NSCLC. qRT-PCR revealed that SLCO4A1-AS1 level was upregulated in NSCLC. Function assays manifested that silence of SLCO4A1-AS1 attenuated NSCLC cell proliferation, migration and invasion but promoted NSCLC cell apoptosis. Furthermore, we disclosed that SLCO4A1-AS1 activated NF-κB pathway in NSCLC, and that IKKα, an NF-κB pathway-related gene, possessed an enhanced level in NSCLC tissues and cells. Importantly, miR-223-3p bound with SLCO4A1-AS1 and IKKα. Further, SLCO4A1-AS1 competitively bound with miR-223-3p to increase IKKα expression, thereby activating NF-κB signaling pathway. In conclusion, SLCO4A1-AS1 drove NSCLC progression by activating NF-κB signaling pathway via sponging miR-223-3p to enhance IKKα expression. Thus, SLCO4A1-AS1 might be a promising biomarker for NSCLC treatment.