A growing body of in vitro and in vivo studies suggests that physical activity offers important benefits against cancer, in terms of both prevention and treatment. However, the exact mechanisms implicated in the anticancer effects of exercise remain to be further elucidated. Muscle-secreted factors in response to contraction have been proposed to mediate the physical exercise-induced beneficial effects and be responsible for the inter-tissue communications. Specifically, myokines and microRNAs (miRNAs) constitute the most studied components of the skeletal muscle secretome that appear to affect the malignancy, either directly by possessing antioncogenic properties, or indirectly by mobilizing the antitumor immune responses. Moreover, some of these factors are capable of mitigating serious, disease-associated adverse effects that deteriorate patients’ quality of life and prognosis. The present review summarizes the myokines and miRNAs that may have potent anticancer properties and the expression of which is induced by physical exercise, while the mechanisms of secretion and intercellular transportation of these factors are also discussed.