A high percentage of patients with lateral ankle sprains report poor outcomes and persistent neuromuscular impairment leading to chronic ankle instability and re-injury. Several interventions have been proposed and investigated, but the evidence on manual therapy combined with therapeutic exercise for pain reduction and functional improvement is still uncertain. The purpose was to study the effectiveness of adding manual therapy to therapeutic exercise in patients with lateral ankle sprains through a critically appraised topic. The literature search was performed in PubMed, PEDro, EMBASE and CINAHL databases, and only randomized clinical trials were included according to following criteria: (1) subjects with acute episodes of lateral ankle sprains, (2) administered manual therapy plus therapeutic exercise, (3) comparisons with therapeutic exercise alone and (4) reported outcomes for pain and function. Three randomized clinical trials (for a total of 180 patients) were included in the research. Meta-analyses revealed that manual therapy plus exercise was more effective than only exercises in improving dorsal (MD = 8.79, 95% CI: 6.81, 10.77) and plantar flexion (MD = 8.85, 95% CI 7.07, 10.63), lower limb function (MD = 1.20, 95% CI 0.63, 1.77) and pain (MD = −1.23; 95% IC −1.73, −0.72). Manual therapy can be used with therapeutic exercise to improve clinical outcome in patients with lateral ankle sprains.