Mouse skeletal muscle stem cells (MuSCs) are functionally heterogeneous, including proliferative capacity and regenerative potential, yet a comprehensive understanding of mechanisms underlying these differences is lacking. Intriguingly, only a subset of muscle groups often succumbs to disease in myopathies. Using a combination of clonal analysis, live imaging and spatiotemporal scRNA-seq, we identified critical regulators of cranial and limb MuSC diversity. Unexpectedly, embryonic and adult extraocular muscle stem cells express distinct ECM and signalling molecules that appear to be regulated by specific transcription factors that constitute a coregulating module throughout development and postnatal growth. These findings provide mechanistic insights into high-performing MuSCs, such as those in the extraocular muscles. They also raise the intriguing possibility that other tissues, like skin and blood that have wide anatomical distributions, could also operate with distinct regulatory properties.