Staphylococcus (S.) epidermidis is a ubiquitous human commensal skin bacterium and prevalent nosocomial pathogen, but genetic factors underlying this lifestyle plasticity are incompletely understood. We developed a large-scale CRISPR interference (CRISPRi) screen complemented by transcriptional profiling (RNA-seq) across 24 conditions and piloted droplet-based CRISPRi. We identified putative essential genes, demonstrated the importance of trace metal uptake under stress, and identified condition-specific essential genes. Additionally, we demonstrate the considerable transcriptional plasticity of S. epidermidis, postulating a mechanism by which nitrogen metabolism is linked to lifestyle versatility in response to hyperosmotic challenges, and performed a comprehensive analysis of survival under acid stress, hypothesizing a role for cell wall modification as crucial. This study represents one of the first large-scale CRISPRi studies in prokaryotes and the first to integrate transcriptomics data across multiple conditions. Our results provide a valuable benchmarking analysis for CRISPRi screens and are rich resource for other staphylococcal researchers.