Although smoking-related diseases, such as chronic obstructive pulmonary disease and heart failure with preserved ejection fraction, are often accompanied by increased peripheral muscle fatigability, the extent to which this is directly caused by cigarette smoke per se is less well understood. Our earlier observation that smoking history did not correlate with fatigability in humans suggests an acute effect caused by carbon monoxide and/or other substances in smoke, hampering skeletal muscle oxygen delivery and mitochondrial function. Indeed, carbon monoxide inhalation acutely and negatively impacts on muscle fatigue. Acutely exposing permeabilized mouse skeletal muscle fibers with smoke extract indicated a clear reduction in the maximal oxidative phosphorylation capacity. These data raise the question whether smoking cessation can be accompanied by beneficial effects on skeletal and cardiac muscle function. Indeed, smoke cessation as short as one to two weeks is associated with improved skeletal muscle structure and mitochondrial function in mice and men. Particularly the diaphragm and cardiac muscle were sensitive to smoke exposure and cessation in mice. Markers of low-grade systemic inflammation reduced in ex-smokers, which was linked to cardiac infiltration of macrophages and fibrosis in mice. Cardiac metabolome analysis revealed altered metabolism, which was partially restored after smoke cessation. Overall, skeletal and cardiac muscle metabolism are acutely altered upon cigarette smoke, and the accompanying systemic inflammation can cause additional skeletal muscle alterations. Smoke cessation quickly restores skeletal muscle mitochondrial function and fatigue resistance.