Objective <p>To investigate the effect of cognitive behavioral therapy on disease uncertainty and stressful life events in glioma patients undergoing chemotherapy.</p> Methods <p>This quasi-experimental study enrolled 90 glioma patients from Sanmenxia Central Hospital between January and December 2021. Patients were divided into an intervention group (<i>n</i> = 45) or a control group (<i>n</i> = 45). The intervention group received cognitive behavioral therapy provided by nurses, while the control group received routine nursing care. Pre- and post-intervention assessments were conducted using the Mishel uncertainty in illness scale (MUIS), life events scale (LES), self-rating anxiety scale (SAS), self-rating depression scale (SDS), and quality of life scale (WHOQOL-BREF).</p> Results <p>After four cycles of chemotherapy, the study group demonstrated a statistically significant decrease in MUIS and LES scores compared to the control group (<i>p</i> &lt; 0.05). The study group showed significantly lower SAS and SDS scores than the control group (<i>p</i> &lt; 0.05). Finally, the study group reported significantly higher WHOQOL-BREF scores than the control group (<i>p</i> &lt; 0.05).</p> Conclusion <p>The study revealed that the group that received CBT showed significant improvements in the psychological well-being of glioma patients undergoing chemotherapy. These findings suggest that incorporating CBT into standard nursing care can effectively improve the psychological well-being and quality of life of glioma patients during chemotherapy.</p>