Interleukin‑12 receptor (IL‑12R) and p38 mitogen‑activated protein kinase (p38MAPK) serve an important role in non‑small cell lung cancer (NSCLC). It has previously been suggested that IL‑12Rβ2 may be involved in key regulatory pathways and interacts with the p38MAPK signaling pathway. The present study aimed to elucidate the possible association and roles of IL‑12Rβ2 and p38MAPK in NSCLC. The protein expression levels of IL‑12Rβ2 and p38MAPK were measured in 230 NSCLC tissue samples by immunohistochemistry (IHC) and western blot analyses. In addition, an immunofluorescence assay was used to observe the expression levels of these proteins in A549 and H358 cells. The associations between IL‑12Rβ2, p38MAPK and clinical characteristics, were evaluated by Pearson χ2 and Spearman correlation tests. Kaplan‑Meier plots (log‑rank test) and Cox proportional hazard models were used to analyze overall survival (OS). Compared with in benign pulmonary tissues, the expression levels of IL‑12Rβ2 and p38MAPK were not demonstrated to be significantly different in I+II pathological tumor‑node‑metastasis (pTNM) stage NSCLC tissues; however, reduced expression was detected in III+IV pTNM stage NSCLC tissues. Analysis of the association between advanced stage pTNM and the expression of both proteins demonstrated a significantly decreased Allred score (both P<0.0001), which was confirmed by IHC and western blot analyses. The IHC results demonstrated a significant correlation between IL‑12Rβ2 and p38MAPK expression (r=0.415, P=0.0143). By analyzing IL‑12Rβ2, p38MAPK expression and clinical characteristics, it was identified that IL‑12Rβ2 was significantly associated with gender (P=0.0168), age (P=0.0341), histological type (P<0.0001) and pTNM stage (P<0.0001). p38MAPK demonstrated a strong association with gender (P=0.0082) and pTNM stage (P<0.0001). The results of a Kaplan‑Meier analysis indicated that positive IL‑12Rβ2 and p38MAPK expression was associated with increased OS compared with negative protein expression. The Cox proportional hazard models revealed that IL‑12Rβ2 and p38MAPK predicted a long OS. To the best of our knowledge, the present study is the first to reveal a close association between IL‑12Rβ2 and p38MAPK, and their possible function in NSCLC progression. It further demonstrated that expression of both proteins was lower with advanced pTNM staging, whereas a high expression of both proteins was associated with improved prognosis in NSCLC.