Objective: It is known that particles released from the prosthesis due to wear after joint replacement surgery affect the lymphatic system. This study aimed to investigate the effect of the manual lymphatic drainage (MLD) technique on pain, edema, and blood lactate dehydrogenase (LDH) levels in the early period of lymphatic transport affected by total knee arthroplasty (TKA). Method: Twenty-four patients who underwent TKA were randomly allocated (control: 12; MLD: 12). Both groups received postoperative rehabilitation. The MLD group also received MLD in the first 3 days after surgery. Clinical assessment was undertaken on the third day and at the sixth week postoperatively. The Visual Analog Scale (VAS) was used for pain during activity, algometer measurements for pain threshold levels, and the Frustum method for leg volumes. The LDH was recorded using laboratory measurements. Results: A significant difference was found in the VAS activity-related pain scores of the groups according to the assessment time (MLD: χ2 = 47.175; p = 0.000; control; χ2 = 30.995; p < 0.000). The pain threshold significantly increased in the MLD group from postoperative day 2 (2nd day, 3rd day, 6th week, respectively; p = 0.015; p = 0.001; p < 0.000). Leg volume significantly decreased over time in both groups after surgery (p < 0.001); however, there was no significant difference between the groups (first-third postoperative days and sixth week; p = 0.192; p = 0.343; p = 0.453; p = 0.908, respectively). While the LDH significantly decreased after drainage in the MLD group (first-third postoperative days; p = 0.002; p = 0.005; p = 0.006, respectively), it increased with exercise in the control group, first day (p = 0.004) and second day (p = 0.019). Conclusions: MLD added to exercise therapy is more effective than exercise therapy alone in reducing the LDH level, a marker of pain and muscle damage, but is not effective for edema due to surgery.