A Structures for Lossless Ion Manipulation-Orbitrap Exploris 480 (SLIM-OE) ion mobility mass spectrometry (IM-MS) platform was developed, integrating SLIM IM separation with Orbitrap MS analysis. A “staggered IMS” mode was designed to acquire IM-m/z two-dimensional heatmap data via direct infusion for method development, and an LC compatible SLIM-enabled data-independent acquisition (SLIM-DIA) workflow was implemented for low sample load proteomics analysis. The study evaluated IM separation across a broad m/z range of ions and demonstrated up to a 190× sensitivity enhancement in both IM-MS and IM-MS/MS modes of operation relative to operation in MS and MS/MS modes, respectively. The increased sensitivity improved protein coverage for the Qual/Quant QC Mix proteins. Compared to standard DIA, SLIM-DIA achieved a 2.3× increase in protein group identification from 2 ng of HeLa on the modified instrument, while maintaining quantitative capabilities. This research highlights the potential of the SLIM-OE IM-MS system to enhance proteomics analysis, providing a foundation for future high-performance SLIM-Orbitrap instrumentation development.