The extracellular-regulated kinase (ERK) 1/2, as a member of the mitogen-activated protein kinase family, plays a crucial role in the development of cancer. However, little is known about the prognostic value of ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2) in non-small cell lung cancer (NSCLC). Thus, we investigated their prognostic values and analyzed the associations between their expressions and clinicopathological features in NSCLC patients. We examined ERK1/2 and p-ERK1/2 expressions via immunohistochemistry in 183 NSCLC samples. The prognostic significances of protein expression were evaluated with univariate and multivariate survival analysis. Of the specimens, 44.8 and 44.3 % revealed positive staining for ERK1/2 and p-ERK1/2, respectively. There were 24.6 % specimens with both ERK1/2 and p-ERK1/2-positive expression. The results showed p-ERK1/2-positive expression was an independent prognostic factor for poor overall survival (OS) in NSCLC patients on both univariate analysis (p < 0.0001) and multivariate analysis (p = 0.0000). Meanwhile, the positive expression of both proteins was also associated with poor OS (p = 0.002). With respect to clinicopathological features, the tumor differentiation was significantly associated with the positivity of ERK1/2, p-ERK1/2, and both proteins, while histological type was only related to ERK1/2. However, there were no significant differences between the expressions and other clinical features, such as gender, age, smoking, tumor-node-metastasis (TNM) stage, lymph node metastasis, and treatments. The p-ERK1/2-positive expression was associated with adverse outcomes, and the positive expression of both ERK1/2 and p-ERK1/2 proteins was also related to poor OS. Therefore, the positivity of p-ERK1/2 expression may serve as a vital biomarker in the development of NSCLC.