Mechanical ventilation (MV) provides life support for critically ill respiratory patients, but in the meantime can cause fatal 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. Recently, it has been reported that 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. It has also been shown that under MV conditions airway smooth muscle cells (ASMC) exhibited abnormal mechanical behaviors, accompanied by regulation of Piezo1 expression and endoplasmic reticulum stress. These reports suggest that MV-induced mechanical abnormality (e.g., hyperresponsiveness or fluidization) ASMC may cause airway collapse and thereby lead to 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 from the cell mechanics perspective to reveal a novel mechanism of MV-associated airway collapse and lung injury. In this review, we first described the phenomenon of airway collapse during MV, then focused on the mechanical behaviors of ASMC under MV and related high stretch, especially the related mechanical-chemical coupling during these processes. Therefore, this article reviewed the recent research progress on airway collapse under MV, changes of ASMC mechanical behavior induced by MV, and related mechanical-chemical coupling mechanisms. These advances may provide novel insights for exploring roles of ASMC mechanical behavior abnormalities in the pathological mechanism of VILI, alternative targets of drug intervention for prevention and/or treatment of VILI as well as for optimizing the ventilation mode in clinical practice.