Objective. To investigate hypoxia-induced Nestin regulates lung cancer viability and metabolism by targeting transcription factors Nrf2, STAT3, and SOX2. Methods. Eighty-four cases of nonsmall cell lung cancer (nonsmall cell lung cancer, NSCLC), which had been treated from June 2020 to February 2021, were randomly selected from our clinicopathology database. Immunohistochemical staining of collected tissue cells was performed to assess the expression patterns of Nestin, STAT3, Nrf2, and SOX2. Data were quantified and statistically analyzed using one-way and two-way ANOVA tests with
P
<
0.05
. Results. Clinicopathological findings showed significant differences in lymph node metastasis, tissue differentiation, and histology on induction of Nestin expression; Nestin expression correlated with STAT3, Nrf2, and SOX2 expression.Nestin/STAT3/SOX2/Nrf2 are involved in angiogenesis and lung cancer development. Conclusion. Hypoxia-induced Nestin promotes the progression of nonsmall lung cancer cells by targeting the downstream transcription factors STAT3, Nrf2, and SOX2.