To evaluate informatics workflows for DIA-based LiP-MS, we generated a high-quality benchmark data set comprising more than 170,000 LiP peptides with defined composition. We then performed comprehensive assessment of major DIA analysis platforms incorporating different spectral libraries, and introduced DIA-LiPQuan, an informatics pipeline tailored to DIA LiP-MS quantification and downstream analysis. Data re-analysis by DIA-LiPQuan with in silico libraries allows sensitive and robust detection of both site-specific structural remodeling of proteins and drug-bound protein targets from the cellular proteome. Collectively, our study provides a valuable benchmark resource and informatics package for LiP-MS data mining, which would facilitate its broader applications in structural proteomics and drug discovery.