<p>Quiescence – the reversible growth-arrested G₀ state – is critical for the long-term maintenance of many adult stem cells and hence the tissues’ life-long regenerative capacity. Failure to maintain stem cell quiescence during aging leads to stem cell loss and reduced ability to regenerate after injury. However, our knowledge about the complex molecular signaling networks required for maintaining stem cells in quiescence is incomplete. Here, we discovered an essential role for FGFR1 and FGFR4 in regulating skeletal muscle stem cell, i.e. satellite cell (SC), quiescence via inhibiting their precocious differentiation. Moreover, SC-specific <i>Fgfr1</i>/<i>4</i>-deficiency results in impaired muscle regeneration and decreased SC self-renewal. Our data reveal that the activated <i>Fgfr1</i>/<i>4</i>-deficient SC-lineage prematurely exits the cell cycle and undergoes terminal differentiation, which is regulated via the ERK signaling axis. This study advances our foundational knowledge on the molecular mechanisms governing SC quiescence, and reveals FGFR1/4 as promising therapeutic targets with the potential to enhance regenerative outcomes in skeletal muscle repair.</p>