Females are less fatigable than males during isometric exercise at intensities relative to maximal voluntary contraction (MVC); however, whether a sex difference in fatigability exists when exercise is prescribed relative to a critical intensity is unknown. This study established the intensity–duration relationship, and compared fatigability and recovery between sexes following intermittent isometric contractions normalised to critical intensity. Twenty participants (10 females) completed four intermittent isometric knee extension trials to task failure to determine critical intensity and the curvature constant (W′), followed by fatiguing tasks at +10% and −10% relative to critical intensity. Neuromuscular assessments were completed at baseline and for 45 min post‐exercise. Non‐invasive neurostimulation, near‐infrared spectroscopy, and non‐invasive haemodynamic monitoring were used to elucidate the physiological mechanisms responsible for sex differences. Females demonstrated a greater critical intensity relative to MVC than males (25 ± 3 vs. 21 ± 2% MVC, P = 0.003), with no sex difference for W′ (18,206 ± 6331 vs. 18,756 ± 5762 N s, P = 0.850). Time to task failure was greater for females (62.37 ± 17.25 vs. 30.43 ± 12.75 min, P < 0.001) during the +10% trial, and contractile function recovered faster post‐exercise (P = 0.034). During the −10% trial females experienced less contractile dysfunction (P = 0.011). Throughout the +10% trial, females demonstrated lesser decreases in deoxyhaemoglobin (P = 0.007) and an attenuated exercise pressor reflex. These data show that a sex difference in fatigability exists even when exercise is matched for critical intensity. We propose that greater oxygen availability during exercise permits females to sustain a higher relative intensity than males, and is an explanatory factor for the sex difference in fatigability during intermittent, isometric contractions.