Objective To explore the changes and clinical significance of serum levels of microtubule-associated protein (Nexilin), Recombinant human Beclin 1 protein (Beclin-1), Complement Clq/tumor necrosis factor related protein 5 (CTRP5) in elderly patients with chronic heart failure. Methods A total of 88 elderly patients with chronic heart failure admitted to Nanyang Rehabilitation Hospital from March 2022 to March 2023 were selected as the observation group, they were divided into grade II, III, and IV according to the New York Heart Association (NYHA) classification of cardiac function. According to the prognosis of the patients after 6 months of treatment, they were divided into good prognosis and poor prognosis groups. In addition, 88 healthy physical examination subjects in the same period were selected as the control group. The levels of serum Nexilin, Beclin-1, and CTRP5 were compared between the two groups, different cardiac function grades, and different prognosis patients. The correlation between serum Nexilin, Beclin-1, and CTRP5 levels and cardiac function grades was analyzed, and the predictive value of combined detection of various indicators for poor prognosis was analyzed. Results The levels of serum Nexilin, Beclin-1, and CTRP5 in the observation group were significantly higher than those in the control group (P<0.05); the levels of serum Nexilin, Beclin-1, and CTRP5 in patients with cardiac function grade IV were significantly higher than those in patients with cardiac function grade III and II, and the levels in patients with cardiac function grade III were higher than those in patients with cardiac function grade II (P<0.05); the levels of serum Nexilin, Beclin-1, and CTRP5 were positively correlated with the classification of cardiac function (P<0.05). Compared with patients with good prognosis, patients with poor prognosis had higher levels of serum Nexilin, Beclin-1, and CTRP5 (P<0.05). The area under the curve (AUC) of the combined prediction of poor prognosis using serum levels of Nexilin, Beclin-1, and CTRP5 was 0.846, with a Youden index of 0.491, a sensitivity of 72.22%, and a specificity of 76.92% (P<0.05). Conclusion The levels of serum Nexilin, Beclin-1, and CTRP5 are closely related to elderly chronic heart failure, which can provide effective reference for clinical prediction of elderly chronic heart failure.