(1) Background: Macrophages undergo polarization, resulting in distinct phenotypes. These transitions, including de-/repolarization, lead to hysteresis, where cells retain genetic and epigenetic signatures of previous states, influencing macrophage function. We previously identified a set of interferon-stimulated genes (ISGs) associated with high lipid levels in macrophages that exhibited hysteresis following M1 polarization, suggesting potential alterations in lipid metabolism; (2) Results: In this study, we applied Weighted Gene Co-expression Network Analysis (WGCNA) and conducted comparative analyses on 162 RNA-seq samples from de-/repolarized and lipid-loaded macrophages, followed by functional exploration; (3) Results: Our results show that in M1 hysteresis, the sustained high expression of Marco and suppression of Abca1/2 reduced lipid efflux, leading to elevated intracellular lipid levels. This accumulation may compensate for reduced cholesterol biosynthesis and provide energy for sustained inflammatory responses and interferon signaling; (4) Conclusions: Our findings elucidate the relationship between M1 hysteresis and lipid metabolism, contributing to understanding the underlying mechanisms of macrophage hysteresis.