Abstract: Phagocytosis, one of the major mechanisms of innate immune defense, is the process by which several types of cells in the immune system recognize, engulf, and digest large particles, such as pathogens and cell debris. In the brain, microglia play phagocytotic roles to regulate the micro-environment of brains under both physiological and pathological conditions. For example, during development, microglia help develop functional synaptic connections by pruning excessively produced synapses. Also, during the recovery phase after brain injury, microglia participate in repairing processes by phagocytosis. The removal of dead/damaged cells by microglia is an important step for brain recovery because compensatory neurogenesis and angiogenesis cannot be fully achieved when the obstacles (i.e., dead cells) remain in the injured brain region. Furthermore, microglia may also participate in pathophysiological mechanisms in brain by secreting soluble factors upon activation. Microglia can release both beneficial and detrimental factors after brain injury depending on the context, but it is still mostly unknown whether and how phagocytotic activity regulates the mechanisms by which microglia produce and secrete these factors. A recent study by our group (Hamanaka et al., 2020) highlights the possibility that the phagocytotic process changes the pattern of the secretome in microglia. At least in in vitro cell culture conditions, microglial response in soluble factor secretion after phagocytosis differs depending on the types of particles/substances that microglia encounter. In this perspective, we briefly introduce the roles of microglia in the brain, focusing on how they contribute to the maintenance of the brain micro-environment, and then we discuss how phagocytosis can regulate soluble factor secretion in microglia. Please note that the reader is encouraged to seek detailed reviews (Underhill and Goodridge, 2012; Fu et al., 2014; Hu et al., 2015; Galloway et al., 2019) that describe and summarize microglial function; due to the space limitation, this perspective does not cite the primary literatures for microglial roles in physiological and pathological conditions.