Swim therapy in the form of moderate physical activity has general health benefits. Regular exercise prevents the progression of chronic diseases affecting the different bodily systems. The metabolic alterations associated with following such lifestyle remain not fully understood. The aim of the present study was to elucidate the metabolic changes following prolonged swim therapy. Twenty-four Sprague Dawley rats were divided into sedentary and exercise groups. Our results revealed that regular exercise significantly increased the serum levels of growth hormone (GH), glucagon and corticosterone. A reduction in the circulating levels of irisin and insulin hormones, and glucose were noticed alongside with an upregulation in the mRNA expression levels of FNDC5, PGC-1α, GLUT-4 and preptin receptors with downregulation in the expression of Enho gene in the heart of exercised rats. Liver of the exercised rats showed elevation in the transcriptional levels of Enho gene, PPARα, and preptin with reduction in the transcriptional levels of preptin receptors. Exercise induced an increase in the pancreatic mRNA of Enho gene, preptin and preptin receptors, and a reduction in FNDC5, PPARα and PGC-1α. An elevation in the gastrocnemius muscle PGC-1α mRNA expression and a decline in the soleus muscle Enho mRNA were found. Exercise diminishes the activities of SOD, CAT and GPx in the gastrocnemius muscle, liver and pancreas. Myogenin expression increased in all examined skeletal muscles. This study takes into account the complex crosstalk between different signaling pathways in skeletal muscles, heart, liver and pancreas as well as the metabolic alterations in response to regular exercise.