Protein homeostasis, or proteostasis, is essential for normal physiological processes in the body. Dysfunctional proteostasis is part of pathogenesis of many diseases and results in increased cell stress and death. Proteostasis is maintained by several quality control systems involved in protein synthesis, degradation, and chaperoning. Ubiquitination modification is one of key regulatory processes that modulate protein turnover and homeostasis and tightly regulated by the opposing actions of ubiquitin E3 ligases and deubiquitinating enzymes (DUBs). Ubiquitination-dependent protein degradation is a crucial process of the proteostasis restoration. Ubiquitination also regulates protein-protein interaction, subcellular localization, and enzyme activities. Coronavirus disease (COVID-19) pandemic has brought lung injury and repair to the forefront of medical attention. Ubiquitination has emerged as a key pathogenic mechanism for the pathogenesis of acute lung injury (ALI) and other lung diseases. Recent studies suggest that the ubiquitin system plays a critical role in lung repair after injury. The current review aims to summarize the recent discoveries regarding the role of key ubiquitin E3 ligases and DUBs in the pathogenesis of acute lung injury, especially focusing on alveolar-capillary disruption, ion transport, fluid clearance, and alveolar inflammation. Novel insights into ubiquitin signaling in lung inflammatory injury may lead to the development of new therapeutic approaches by targeting specific elements of the ubiquitin pathways.