Mechanical ventilation (MV) provides life support for critically ill respiratory patients, but in the meantime can cause fatal ventilator-induced lung injury (VILI), and the latter remains a major challenge in respiratory and critical care medicine, because the pathological mechanism has not been fully elucidated. Recent studies show that on the one hand, in the lung with VILI, there exists airway collapse at multi-sites of an individual airway, which can not be explained by traditional airway collapse models. But on the other hand, under MV conditions, airway smooth muscle cells (ASMC) exhibit abnormal mechanical behaviors, accompanied by regulation of Piezo1 expression and endoplasmic reticulum stress. These phenomenons indicate that the MV-induced abnormal mechanical behavior of ASMC is closely related to multiple airway collapse and VILI. Therefore, by studying the MV-induced changes of ASMC mechanical behaviors and their relationship with airway collapse in lung injury, as well as the related mechanochemical signal coupling process, it is expected to reveal a novel mechanism of MV-associated airway collapse and lung injury from the perspective of cell mechanics. In this review, the recent research progress of airway collapse during MV, the regulation of ASMC mechanical behavior by MV-related high stretch, especially the related mechanochemical signal coupling mechanism is summarized. These advances may provide a novel insight for exploring the roles of ASMC abnormal mechanical behavior in the pathological mechanism of VILI, alternative targets of drug intervention for prevention and treatment of VILI, as well as for optimizing the ventilation mode in clinical practice.