Oligodendrocyte precursor cells (OPCs) serve as progenitors for oligodendrocytes (OLs) throughout their life, contributing to developmental and adaptive myelination, as well as myelin repair. OPCs are known to make synaptic and extra-synaptic contacts with axons, but the mechanisms by which they integrate the information relayed by the neuronal activity into Ca2+ signals, which in turn influence their fate and survival, are still unclear. Using newly developed transgenic mouse lines to express genetically encoded Ca2+ sensors in OPCs, we performed 2-photon microscopy in the somatosensory cortex of awake freely-moving mice while monitoring intracellular Ca2+ signals and cell-fate progression simultaneously. We found that Ca2+ signals in OPCs mainly occur within processes and are confined to micrometer-size segments called Ca2+ microdomains. We uncovered that OPCs exhibit distinct signatures of Ca2+ signals during fate progression, and that their baseline Ca2+ activity is significantly reduced as OPCs transition from premyelinating to mature OLs. Also, we found that OPCs with globally reduced Ca2+ activity tend to proliferate, while OPCs with enhanced Ca2+ signals differentiated into OLs. In line with this observation, a chemogenetic increase in OPCs Ca2+ signals or enhanced neuronal activity promoted the differentiation of OPCs into OLs. Taken together, our data suggest that different cell types within the oligodendrocyte lineage exhibit unique Ca2+ signatures, and integrate these Ca2+ signals to direct their fate decisions and lineage progression.