Background: Considering the lengthy recovery and high recurrence risk after a hamstring injury, effective rehabilitation and accurate prognosis are fundamental to timely and safe return to play (RTP) for athletes. Purpose: To analyze methods of rehabilitation for acute proximal and muscular hamstring injuries and summarize prognostic factors associated with RTP. Study Design: Systematic review; Level of evidence, 4. Methods: In August 2020, MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials, and SPORTDiscus were queried for studies examining management and factors affecting RTP after acute hamstring injury. Included were randomized controlled trials, cohort studies, case-control studies, and case series appraising treatment effects on RTP, reinjury rate, strength, flexibility, hamstrings-to-quadriceps ratio, or functional assessment, as well as studies associating clinical and magnetic resonance imaging factors with RTP. Risk of bias was assessed using the Cochrane Risk-of-Bias Tool for Randomized Trials or the Methodological Index for Non-Randomized Studies (MINORS). Results: Of 1289 identified articles, 75 were included. The comparative and noncomparative studies earned MINORS scores of 18.8 ± 1.3 and 11.4 ± 3.4, respectively, and 12 of the 17 randomized controlled trials exhibited low risk of bias. Collectively, studies of muscular injury included younger patients and a greater proportion of male athletes compared with studies of proximal injury. Surgery for proximal hamstring ruptures achieved superior outcomes to nonoperative treatment, whereas physiotherapy incorporating eccentric training, progressive agility, and trunk stabilization restored function and hastened RTP after muscular injuries. Platelet-rich plasma injection for muscular injury yielded inconsistent results. The following initial clinical findings were associated with delayed RTP: greater passive knee extension of the uninjured leg, greater knee extension peak torque angle, biceps femoris injury, greater pain at injury and initial examination, “popping” sound, bruising, and pain on resisted knee flexion. Imaging factors associated with delayed RTP included magnetic resonance imaging-positive injury, longer lesion relative to patient height, greater muscle/tendon involvement, complete central tendon or myotendinous junction rupture, and greater number of muscles injured. Conclusion: Surgery enabled earlier RTP and improved strength and flexibility for proximal hamstring injuries, while muscular injuries were effectively managed nonoperatively. Rehabilitation and athlete expectations may be managed by considering several suitable prognostic factors derived from initial clinical and imaging examination.