Performance fatigability is characterized by a decline in the capacity to maintain force or power during sustained or repeated activity. This exploratory study quantified knee-extensor mechanical performance and rectus femoris surface electromyographic (sEMG) changes during repeated maximal isokinetic knee extensions and explored sex-related differences. Twenty-nine healthy adults (20 men, 9 women; 20–31 years) performed 30 maximal concentric knee extensions at 180°·s⁻¹. Mechanical outcomes were analyzed in all 29 participants, whereas rectus femoris sEMG outcomes were analyzed in 23 participants. Peak torque (PT) decreased by 32.75 ± 11.66% (adjusted p = 6.08 × 10⁻¹¹), work per repetition by 33.35 ± 11.97% (adjusted p = 2.12 × 10⁻¹¹), and mean frequency (MNF) by 23.44 ± 8.33% (adjusted p = 6.08 × 10⁻¹¹). RMS increased significantly from Start to End (adjusted p = 0.000639), with a mean FI-RMS of −17.12 ± 23.11%. FI-PT and FI-work were very strongly associated (ρ = 0.938, adjusted p = 3.71 × 10⁻¹³), whereas no association involving rectus femoris MNF or RMS remained statistically significant after Holm–Bonferroni correction. No statistically significant sex-related differences were detected. Repeated maximal knee extensions reduced mechanical performance and rectus femoris MNF while increasing RMS. FI summarizes Start-to-End change across the measured outcomes; its reliability and validity require further investigation.