Objective To evaluate the efficacy of Cognitive Behavioral Therapy for Insomnia (CBT-I) combined with zolpidem in improving sleep disorders and cognitive function in patients with Alzheimer's disease (AD).Methods This retrospective study included 120 AD patients with sleep disorders admitted to the Department of Psychology, Taizhou People’s Hospital, from March 2019 to January 2024. Patients were divided into a control group (n = 60) and an observation group (n = 60) based on treatment methods. The control group received oral zolpidem tartrate tablets, while the observation group received CBT-I combined with zolpidem for 4 weeks. Polysomnography (PSG) parameters were monitored. Sleep quality, mental status (MMSE), cognitive function (ADAS-cog), serum neurotransmitter levels (5-HT, BDNF, SP, DA), and inflammatory factors (IL-1β, IL-6, IL-10, CRP, TNF-α) were measured before and after treatment using enzyme-linked immunosorbent assay (ELISA).Results Post-treatment, the observation group showed significantly greater reductions in sleep latency and number of awakenings, as well as a greater increase in total sleep time compared to the control group (P < 0.05). Sleep quality scores decreased more markedly in the observation group (P < 0.05). MMSE scores increased and ADAS-cog scores decreased more significantly in the observation group (P < 0.05). Serum levels of 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF), and dopamine (DA) increased more substantially in the observation group, while substance P (SP) decreased more markedly (P < 0.05). Reductions in interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-10 (IL-10), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) were also greater in the observation group (P < 0.05).Conclusion CBT-I combined with zolpidem significantly improves sleep quality, cognitive function, and mental status in AD patients with sleep disorders by modulating serum neurotransmitters and inflammatory factors. This dual therapy may act through multiple mechanisms to enhance quality of life and cognitive outcomes.