ObjectiveTo evaluate the effectiveness of interventions to prevent and manage knee injuries in runners.DesignSystematic review and meta-analysis.Data sourcesMEDLINE, EMBASE, CINAHL, Web of Science and SPORTDiscus up to May 2022.Eligibility criteria for selecting studiesRandomised controlled trials (RCTs) with a primary aim of evaluating the effectiveness of intervention(s) to prevent or manage running-related knee injury.ResultsThirty RCTs (18 prevention, 12 management) analysed multiple interventions in novice and recreational running populations. Low-certainty evidence (one trial, 320 participants) indicated that running technique retraining (to land softer) reduced the risk of knee injury compared with control treadmill running (risk ratio (RR) 0.32, 95% CI 0.16 to 0.63). Very low-certainty to low-certainty evidence from 17 other prevention trials (participant range: 24 –3287) indicated that various footwear options, multicomponent exercise therapy, graduated running programmes and online and in person injury prevention education programmes did not influence knee injury risk (RR range: 0.55–1.06). In runners with patellofemoral pain, very low-certainty to low-certainty evidence indicated that running technique retraining strategies, medial-wedged foot orthoses, multicomponent exercise therapy and osteopathic manipulation can reduce knee pain in the short-term (standardised mean difference range: −4.96 to −0.90).ConclusionThere is low-certainty evidence that running technique retraining to land softer may reduce knee injury risk by two-thirds. Very low-certainty to low-certainty evidence suggests that running-related patellofemoral pain may be effectively managed through a variety of active (eg, running technique retraining, multicomponent exercise therapy) and passive interventions (eg, foot orthoses, osteopathic manipulation).PROSPERO registration numberCRD42020150630