Reproductive systems and their associated hormonal networks are highly sensitive to metabolic status. Although adipose tissue has traditionally been considered the primary metabolic regulator of reproduction, emerging evidence supports skeletal muscle-derived myokines, including myostatin (1), also influence reproductive physiology. Here, we hypothesised that caloric restriction (CR)-induced changes in skeletal muscle myokine secretion contribute to reproductive endocrine dysfunction in female mice. Firstly, 24-week-old female C57BL/6J mice underwent graded CR, to 65% of starting food intake across 5 weeks, alongside age-matched ad libitum-fed controls. CR females exhibited significant reductions in body mass (-10%, p < 0.0001) and lean mass (-15%, p < 0.0001), but surprisingly no loss of fat mass relative to controls. Histological analyses of tibialis anterior and soleus muscles revealed reduced myofibre cross-sectional area and diameter in CR females (p < 0.05), without changes in fibre-type composition. Intriguingly, serum analyses demonstrated a 31% increase in circulating myostatin levels in CR females (p < 0.05). In parallel with these muscular changes, CR induced profound reproductive dysfunction, including an arrest of oestrous cycling and marked reductions in ovarian (-43%, p < 0.0001) and uterine weights (-75%, p < 0.001). Consistent with a suppression of ovarian folliculogenesis, RT-qPCR analyses revealed a ten-fold upregulation of pituitary Fshβ (FSH b-subunit) expression (p < 0.001). Further bulk RNA sequencing analysis revealed major endocrine remodelling in response to energy deficit (2240 differentially expressed genes). To test whether myokines directly regulate pituitary hormone synthesis, we cultured primary murine pituitary cells in CR skeletal muscle extracellular fluid. RT-qPCR analysis of these cultured cells demonstrated an upregulation of Fshβ expression (p < 0.05) with CR myokine treatment. Collectively, these findings demonstrate that CR-induced skeletal muscle adaptations are associated with disruptions in female reproductive function in mice, highlighting a potential regulatory role for muscle-derived myokines in modulating reproductive capacity.