PZR is a transmembrane glycoprotein encoded by theMPZL1gene. It serves as a specific binding protein and substrate of tyrosine phosphatase SHP-2 whose mutations cause developmental diseases and cancers. Bioinformatic analyses of cancer gene databases revealed that PZR is overexpressed in lung cancer and correlated with unfavorable prognosis. To investigate the role of PZR in lung cancer, we employed the CRISPR technique to knockout its expression and recombinant lentiviruses to overexpress it in lung adenocarcinoma SPC-A1 cells. While knockout of PZR reduced colony formation, migration, and invasion, overexpression of PZR had the opposite effects. Furthermore, when implanted in immunodeficient mice, PZR-knockout SPC-A1 cells showed suppressed tumor-forming ability. Finally, the underlying molecular mechanism for these functions of PZR is its positive role in activating tyrosine kinases FAK and c-Src and in maintaining the intracellular level of reactive oxygen species (ROS). In conclusion, our data indicated that PZR plays an important role in lung cancer development, and it may serve as a therapeutic target for anti-cancer development and as a biomarker for cancer prognosis.