Background <p>Type 2 Diabetes Mellitus (T2DM) is linked to increased risk of neurocognitive decline, depressive symptoms, and diminished quality of life (QoL). Neuroinflammatory mechanisms and deregulation of the Wnt signaling pathway may contribute to these complications. The purpose of this study is to examine the involvement of Wnt signaling pathway along with neuroinflammatory biomarkers during cognitive impairment and depression in T2DM patients.</p> Methods <p>A single centre case-control study was conducted involving 128 participants, including 64 T2DM patients and 64 healthy volunteers. Demographic, clinical, and biochemical data were collected. Cognitive function, depression and QoL were assessed using Montreal Cognitive Assessment (MoCA), Patient Health Questionnaire-9 (PHQ-9), and World Health Organization Quality of Life-Brief version (WHOQOL-BREF) standardized tests respectively. Serum levels of interleukin-6 (IL-6), interleukin-1ꞵ (IL-1ꞵ), tumor necrosis factor-α (TNF-α), Wingless-Type-1 (Wnt1), porcupine (PORCN), and R-Spondin-2 (RSPO2) were measured using ELISA.</p> Results <p>T2DM patients showed significantly reduced scores in MoCA, higher scores in PHQ-9 and reduced WHOQOL-BREF scores compared to healthy controls. Serum IL-1ꞵ were significantly elevated, while serum Wnt1, PORCN and RSPO2 levels were significantly reduced in T2DM group. ROC analysis revealed excellent diagnostic accuracy for IL-1ꞵ and good discriminatory performance for Wnt1, PORCN and RSPO2.</p> Conclusion <p>T2DM patients indicated cognitive impairment, depressive symptoms with reduced QoL. The presence of neuroinflammation and impaired Wnt signaling pathway suggest a potential biological link underlying neurobehavioral complications in T2DM. Considering the increasing burden of diabetes related neurobehavioral complication, integration of Wnt signaling and neuroinflammatory biomarkers into research may enhance early identification and facilitate appropriate and timely intervention strategies.</p>