Background: Retrograde drilling (RD) is a minimally invasive surgical procedure mainly used for non-displaced osteochondral lesions (OCL) of the talus, dealing with subchondral necrotic sclerotic lesions or subchondral cysts without inducing iatrogenic articular cartilage injury, allowing the revascularization of the subchondral bone and new bone formation. Methods: This systematic review collected and analyzed the clinical studies of the last 10 years of literature, focusing not only on the clinical results but also on patients’ related factors (gender, BMI, age and complications). Results: Sixteen clinical studies were retrieved, and differences in the type of study, follow-up, number and age of patients, lesion type, dimensions, grades and comparison groups were observed, making it difficult to draw conclusions. Nevertheless, lesions on which RD showed the best results were those of I–III grades and not exceeding 150 mm2in size, showing overall positive results, a good rate of patient satisfaction, improvements in clinical scores, pain reduction and return to daily activities and sports. Conclusions: There are still few studies dealing with the issue of post-surgical complications and gender-related responses. Further clinical or preclinical studies are thus mandatory to underline the success of this technique, also in light of gender differences.