Prolonged treatment resistant quadriceps weakness after anterior cruciate ligament reconstruction (ACL-R) contributes to re-injury risk, poor patient outcomes, and earlier development of osteoarthritis. The origin of post-injury weakness is in part neurological in nature, but it is unknown whether regional brain activity is related to clinical metrics of quadriceps weakness. Thus, the purpose of this investigation was to better understand the neural contributions to quadriceps weakness after injury by evaluating the relationship between brain activity for a quadriceps-dominated knee task (repeated cycles of unilateral knee flexion/extension from 45° to 0°), , and strength asymmetry in individuals returned to activity after ACL-R. Forty-four participants were recruited (22 with unilateral ACL reconstruction; 22 controls) and peak isokinetic knee extensor torque was assessed at 60°/s to calculate quadriceps limb symmetry index (Q-LSI, ratio of involved/uninvolved limb). Correlations were used to determine the relationship of mean % signal change within key sensorimotor brain regions and Q-LSI. Brain activity was also evaluated group wise based on clinical recommendations for strength (Q-LSI < 90%, n = 12; Q-LSI ≥ 90%, n = 10; controls, all n = 22 Q-LSI ≥ 90%). Lower Q-LSI was related to increased activity in the contralateral premotor cortex and lingual gyrus (p< .05). Those who did not meet clinical recommendations for strength demonstrated greater lingual gyrus activity compared to those who met clinical recommendations Q-LSI ≥ 90 and healthy controls (p< 0.05). Asymmetrically weak ACL-R patients displayed greater cortical activity than patients with no underlying asymmetry and healthy controls.