Lung cancer is one of the most deadly tumor disease in the world and most lung cancer is non-small cell lung cancer. MicroRNAs are considered as a variety of endogenous non-coding RNA, acting as interference during the process after transcription of gene. Recently, microRNA-142-5p, one of the microRNAs, was reported to enhance anti-tumor immune of non-small cell lung cancer cells by targeting programmed cell death receptor ligand 1. Programmed cell death receptor ligand 1 was also believed to be a regulator of cell proliferation and migration. However, the effect of microRNA-142-5p on proliferation and invasion of non-small cell lung cancer cells via regulating programmed cell death receptor ligand 1 was still unknown. Thus, this study demonstrated that there was low expression level of microRNA-142-5p in different nonsmall cell lung cancer cell lines. Programmed cell death receptor ligand 1 was proved to be the target gene of microRNA-142-5p and microRNA-142-5p also had negative correlation with programmed cell death receptor ligand 1. The high expression of microRNA-142-5p lead to suppression of proliferation and invasion in non-small cell lung cancer cells by down regulation of programmed cell death receptor ligand 1. The mechanism of microRNA-142-5p affecting proliferation and invasion of non-small cell lung cancer cells via targeting programmed cell death receptor ligand 1 might give a new thought of tumor therapy.