Coronavirus disease 2019 (Covid-19) is an evolving pandemic that threatens public health in the whole world. The current therapy for critically ill Covid-19 patients in the intensive care unit (ICU) relay on mechanical ventilation (MV) to provide respiratory and life support. However, MV is also known to induce lung injury, which is called ventilator-induced lung injury (VILI). Clinical studies indicate an extraordinarily high mortality rate (>50%) for those Covid-19 patients underwent MV in ICU, suggesting a link between the high mortality rate and the mechanical stretch during MV considering the mechanical nature of MV. Thus, it is imperative to understand the MV-induced pathological alterations in the respiratory system and corresponding mitigation measures in order to improve the treatment of critically ill Covid-19 patients. Therefore, we briefly reviewed the situation of Covid-19, and then summarized the biomechanical risk factors and their roles and mechanisms related lung injuries during MV, including changes in respiratory parameters, inflammatory cytokines storm, ciliary-mucus system, airway smooth muscle cells, lung fibrosis, and stretch-activated cell signaling. It is hoped that these biomechanical questions can be greatly attended and investigated, of which the findings can provide insights for optimizing the therapy for Covid-19 as well as other respiratory diseases.