Knee trauma can lead to poor health-related quality of life (HRQoL) and osteoarthritis. We aimed to assess HRQoL 3–12 years following youth sport-related knee injury considering HRQoL and osteoarthritis determinants. Generic (EQ-5D-5L index, EQ-VAS) and condition-specific (Knee injury and Osteoarthritis Outcome Score quality of life subscale, KOOS QOL) HRQoL were assessed in 124 individuals 3–12 years following youth sport-related knee injury and 129 uninjured controls of similar age, sex, and sport. Linear regression examined differences in HRQoL outcomes by injury group. Multivariable linear regression explored the influence of sex, time-since-injury, injury type, body mass index, knee muscle strength, Intermittent and Constant Osteoarthritis Pain (ICOAP) score, and Godin Leisure-Time Exercise Questionnaire (GLTEQ) moderate-to-strenuous physical activity. Participant median (range) age was 23 years (14–29) and 55% were female. Injury history was associated with poorer KOOS QOL (−8.41; 95%CI −10.76, −6.06) but not EQ-5D-5L (−0.0074; −0.0238, 0.0089) or EQ-VAS (−3.82; −8.77, 1.14). Injury history (−5.14; −6.90, −3.38), worse ICOAP score (−0.40; −0.45, −0.36), and anterior cruciate ligament tear (−1.41; −2.77, −0.06) contributed to poorer KOOS QOL. Worse ICOAP score contributed to poorer EQ-5D-5L (−0.0024; −0.0034, −0.0015) and higher GLTEQ moderate-to-strenuous physical activity to better EQ-VAS (0.10; 0.03, 0.17). Knee trauma is associated with poorer condition-specific but not generic HRQoL 3–12 years post-injury.