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Microglia play important roles during physiological and pathological situations in the CNS. Several reports have described the expression of <i>Cd74</i> in disease-associated and aged microglia. Here, we demonstrated that TGFβ1 controled the expression of <i>Cd74</i> in microglia in vitro and in vivo. Using BV2 cells, primary microglia cultures as well as <i>Cx3cr1^CreERT2:R26-YFP:Tgfbr2^fl/fl</i> in combination with qPCR, flow cytometry, and immunohistochemistry, we were able to provide evidence that TGFβ1 inhibited LPS-induced upregulation of <i>Cd74</i> in microglia. Interestingly, TGFβ1 alone was able to mediate downregulation of CD74 in vitro. Moreover, silencing of TGFβ signaling in vivo resulted in marked upregulation of CD74, further underlining the importance of microglial TGFβ signaling during regulation of microglia activation. Taken together, our data indicated that CD74 is a marker for activated microglia and further demonstrated that microglial TGFβ signaling is important for regulation of <i>Cd74</i> expression during microglia activation.