The mechanophysiological conditions of injured skin greatly influence the degree of scar formation, scar contracture, and abnormal scar progression/generation (e.g., keloids and hypertrophic scars). It is important that scar mechanobiology be understood from the perspective of the extracellular matrix and extracellular fluid, in order to analyze mechanotransduction pathways and develop new strategies for scar prevention and treatment. Mechanical forces such as stretching tension, shear force, scratch, compression, hydrostatic pressure, and osmotic pressure can be perceived by two types of skin receptors. These include cellular mechanoreceptors/mechanosensors, such as cytoskeleton (e.g., actin filaments), cell adhesion molecules (e.g., integrin), and mechanosensitive (MS) ion channels (e.g., Ca2+ channel), and sensory nerve fibers (e.g., MS nociceptors) that produce the somatic sensation of mechanical force. Mechanical stimuli are received by MS nociceptors and signals are transmitted to the dorsal root ganglia that contain neuronal cell bodies in the afferent spinal nerves. Neuropeptides are thereby released from the peripheral terminals of the primary afferent sensory neurons in the skin, modulating scarring via skin and immune cell functions (e.g., cell proliferation, cytokine production, antigen presentation, sensory neurotransmission, mast cell degradation, vasodilation, and increased vascular permeability under physiological or pathophysiological conditions). Mechanoreceptor or MS nociceptor inhibition and mechanical force reduction should propel the development of novel methods for scar prevention and treatment.