Little is known regarding the functional role of microRNA-195-5p (miR-195-5p) in heart failure (HF). Hence, the aim of the present study was to investigate the effect of miR-195-5p on cardiac function in mice with HF and its mechanism through the regulation of Chemokine receptor type 4 (CXCR4) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. The mice model of HF was established by transverse aortic constriction, the successfully modeled mice were injected with anti-miR-195-5p and OE-CXCR4. The expression of miR-195-5p, CXCR4, JAK2 and STAT1 in the myocardial tissues of each group were detected. The target relationship between miR-195-5p and CXCR4 was verified. The indices of cardiac ultrasound, hemodynamics, oxidative stress, inflammatory factor, myocardial enzyme and cardiac function were detected. MiR-195-5p, JAK2 and STAT1 expression were raised and CXCR4 expression was degraded in myocardial tissues of HF mice and CXCR4 was the target gene of miR-195-5p. Down-regulated miR-195-5p and up-regulated CXCR4 ameliorated cardiac function, abated inflammatory factors contents, oxidative stress reaction and myocardial enzyme indices in HF mice. Down-regulated miR-195-5p and up-regulated CXCR4 suppressed apoptosis of cardiomyocytes in HF mice. Depleting miR-195-5p and up-regulating CXCR4 alleviates cardiac function injury in mice with HF via inhibition of JAK/STAT signaling pathway activation. MiR-195-5p might be a potential candidate marker and therapeutic target for HF. Copyright © 2020. Published by Elsevier B.V.