Self-efficacy refers to an individual’s belief in their ability to successfully manage and overcome challenging situations. It is a key factor that can help patients effectively cope with anxiety. Anxiety is a common emotional response experienced by patients during hospitalization, and high levels of anxiety can negatively impact comfort, the healing process, and overall quality of life. Psychological interventions such as Cognitive Behavioral Therapy (CBT) have been shown to improve self-efficacy and significantly reduce anxiety. This study aimed to evaluate the effect of CBT in enhancing self-efficacy and reducing anxiety levels in hospitalized patients. A quasi-experimental design with a control group and pre-test post-test measurements was used. The study involved 45 respondents, selected through a saturated sampling technique, meaning all eligible participants who met the inclusion criteria were included. Data were analyzed using the Wilcoxon signed-rank test. The results showed that all respondents in the intervention group had consistently high self-efficacy before and after CBT. CBT significantly improved patients’ confidence in managing their treatment period (p-value 0.000) and meaningfully reduced their anxiety levels (p-value 0.000). In contrast, the control group showed no change in self-efficacy (p-value 1.000) and experienced a slight increase in anxiety (p-value 0.257). These findings highlight the positive impact of CBT in helping patients feel stronger, calmer, and more in control during hospitalization. CBT is recommended as part of a holistic and compassionate approach to patient care in clinical settings.