Dysfunctional white adipose tissue contributes to the development of obesity-related morbidities, including insulin resistance. Adipose tissue macrophages (ATMs) accumulate in obesity and play beneficial and harmful roles in adipose tissue homeostasis and remodeling. Despite their importance, the molecules and mechanisms that regulate these diverse functions are not well understood. CD9 is a tetraspanin molecule with various cellular functions including adhesion, signal transduction, and extracellular vesicle (EV) biogenesis. CD9 was previously identified as a surface marker of proinflammatory obesity-associated ATMs. However, its role in ATMs is unknown. Given that CD9 has diverse functions, we hypothesized that CD9 may regulate ATMs in both cell-intrinsic and cell-extrinsic manners. Herein, we 1) interrogate a novel mouse model of myeloid-specific CD9 deficiency during obesity to understand the cell-intrinsic roles of CD9 in ATMs and 2) investigate a model of liver-specific CD9 deficiency during obesity to understand the role of CD9 in liver-adipose tissue interorgan communication. We find that cell-intrinsic CD9 regulates the adhesion of ATMs to adipocytes, contributing to crown-like structure formation. Furthermore, cell-intrinsic CD9 regulates the expression of pro-fibrotic and extracellular matrix remodeling genes. Deletion of CD9 in myeloid cells results in decreased adipose tissue fibrosis, increased visceral adipose tissue accumulation, and improved global metabolic outcomes during obesity. These results identify cell-intrinsic CD9 as a regulator of pathogenic features of ATMs and a potential therapeutic target for treating obesity-associated morbidities. In contrast, we find that deletion of liver-derived CD9 leads to increased susceptibility to obesity-associated sequelae, including adipose tissue dysfunction, glucose intolerance, ectopic lipid deposition, and hyperlipidemia. Furthermore, deletion of liver-derived CD9 exacerbates adipose tissue inflammation, including increased accumulation and proinflammatory activation of ATMs. Moreover, hepatocyte-derived EVs promote anti-inflammatory activation of macrophages in a CD9-dependent manner. These results suggest that CD9-dependent hepatocyte-derived EVs may play a role in maintaining an anti-inflammatory activation state, ultimately protecting against the development of obesity-associated sequelae. Overall, these findings demonstrate that depending on its cellular origin, CD9 plays both beneficial and pathologic roles in ATM activation and obesity-associated metabolic dysfunction.