The study investigated the effects of esketamine combined with quadratus lumborum block (QLB) on postoperative anxiety, depression, and cognitive function in frail elderly patients undergoing radical surgery for colorectal cancer. Patients were randomly divided into a control group with standard anesthesia and a combined group with QLB and esketamine. Both groups had the same values of mean arterial pressure (MAP) and heart rate (HR) before anesthesia induction (p > 0.05). After induction, during pneumoperitoneum and after surgery, the combined group had significantly lower MAP and HR (p < 0.05). The combination group required lower doses of remifentanil and propofol (p < 0.05), had shorter recovery times, and lower agitation scores upon awakening (p < 0.05). On postoperative days 1 and 3, the combined group had higher Mini-Mental State Examination (MMSE) scores (p < 0.05) and lower visual analog scale (VAS) pain scores at 1, 4, and 12 hours after extubation (p < 0.05). The combination reduces postoperative cognitive dysfunction and pain.