Smoking has been considering a crucial factor in promoting skin and systemic aging that is associated with the development of a low-level, systemic, chronic inflammation known as "inflammaging" in which monocytes play a pivotal role. Our aim was to investigate the effects of AM3 plus antioxidants vs placebo in the activation status, function of monocytes and cutaneous aging parameters in healthy smoker middle-aged women. A total of 32 women were 1:1 randomly assigned to AM3 plus antioxidants or placebo for three months. Peripheral mononuclear blood cells and cutaneous biopsy were obtained and flow cytometry and immunohistological studies, respectively, were performed before and after the treatment. AM3 plus antioxidants treatment compared with placebo significantly reduced the monocyte production of the proinflammatory interleukin 1 (IL-1), tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) cytokines as well as increased the regulatory IL-10 in middle-aged smoker women. Furthermore, AM3 and antioxidants did not modify ROS production by monocytes and granulocytes but increased their phagocytic activity. The active combination also stimulated a significative increase in reticular dermis depth as well as an increase in the expression of CD117 and CD31. Thus, AM3 and antioxidants treatment reduces the systemic proinflammatory monocyte disturbance of heathy smoker middle-aged women and encourage skin repair mechanisms.