This study investigates the molecular responses to endurance exercise training in male and female rats over eight weeks. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled multiple omics platforms in whole blood, plasma, and 18 solid tissues. The analysis revealed extensive molecular alterations, including changes in immune, metabolic, stress response, and mitochondrial pathways. These changes were tissue-specific and sex-differentiated, with many relevant to human health conditions such as non-alcoholic fatty liver disease, inflammatory bowel disease, and cardiovascular health. The study provides a comprehensive resource for understanding the molecular mechanisms underlying the benefits of endurance exercise and highlights the importance of multi-omic approaches in studying exercise-induced adaptations. The data and analyses are available in a public repository, offering valuable insights for future research on exercise and health.This study investigates the molecular responses to endurance exercise training in male and female rats over eight weeks. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled multiple omics platforms in whole blood, plasma, and 18 solid tissues. The analysis revealed extensive molecular alterations, including changes in immune, metabolic, stress response, and mitochondrial pathways. These changes were tissue-specific and sex-differentiated, with many relevant to human health conditions such as non-alcoholic fatty liver disease, inflammatory bowel disease, and cardiovascular health. The study provides a comprehensive resource for understanding the molecular mechanisms underlying the benefits of endurance exercise and highlights the importance of multi-omic approaches in studying exercise-induced adaptations. The data and analyses are available in a public repository, offering valuable insights for future research on exercise and health.