Abstract: To explore the mechanism of phycocyanin in inhibiting the proliferation and migration of LTEP-a2 non-small cell lung cancer cells, a high-throughput miRNA transcription set (miRNA-Seq) was performed to screen differential miRNAs in the cells treated by phycocyanin. An in-vitro over-expression mimic method was taken to verify the proliferation and migration ability of differential miRNA in LTEP-a2 cells. Analysis results show that phycocyanin can improve the expression of miR-642a-5p in LTEP-a2 cells. Over-expression of miR-642a-5p can obviously decrease the proliferation and migration ability of LTEP-a2 cells. Phycocyanin can activate NF-κB signaling pathway by up-regulating miR-642a-5p expression, reduce protein phosphorylation level, and then inhibit the proliferation and migration of LTEP-a2 cells. The results provide a theoretical basis for the application of phycocyanin and the treatment of non-small cell lung cancer.