Autophagy and phagocytosis are critical processes involved in maintaining macrophage homeostasis and cellular immunity. Because dysfunction of autophagy is observed in many human pathologies, it is important to understand the regulatory mechanisms governing crosstalk between autophagy and phagocytosis. Glia maturation factor-gamma (GMFg) is a novel regulator of the Arp2/3 complex, its role in modulating autophagy and phagocytosis remains unknown. Here, we show that knockdown of GMFg in murine macrophages inhibited autophagosome formation and compromised lysosomal function. GMFg knockdown suppressed phosphorylation of liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling pathway components, suggesting a role for this pathway in GMFg regulation of autophagy. Moreover, GMFg-knockdown macrophages displayed increased the expression of scavenger-receptor MSR1 and CD36, which was dependent on activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, and exhibited increased phagocytic activity. In contrast, overexpression of GMFg in murine macrophages increased autophagosome abundance and suppressed both scavenger-receptor expression and phagocytic activity. These findings suggest that GMFg regulates autophagy through AMPKregulated control of autophagosome formation, while mediating phagocytosis through modulation of scavenger-receptor abundance in macrophages, and may provide insight into therapeutic approaches to autophagy-related diseases and autophagy-regulated phagocytosis in immune and metabolic disorders.