Background Pain control after total knee arthroplasty (TKA) is important for early postoperative experience and knee rehabilitation. However, there is no consensus on the Pain management after TKA. Whether early analgesic effect and patient satisfaction can reach or even exceed the femoral nerve block has been controversial. The aim of our study was to compare the early analgesia effect with multimodal cocktail periarticular injection (MCPI) and Femoral nerve block (FNB) during simultaneous knee arthroplasty. Methods Our study was a prospective randomized, double-blind controlled trial. From December 2018 to August 2019, 85 patients (170 knees) who underwent bilateral total knee arthroplasty at our institution were randomly treated with MICP and FNB. Randomization was done via a computerized randomization list. The visual analogue scores for pain, bilateral knee range of motion (ROM), postoperative adverse events, and patients satisfaction were assessed preoperatively and two weeks postoperatively. This trial is registered at ClinicalTrials.gov, number ChiCTR1800020003. Results A total of 85 patients (170 knees) were enrolled for bilateral TKA. Finally, 80 (160 knees) patients were included for analysis and comparison. The operation time of the MCPI group was significantly lower than the FNB group (66.5±8.7 min compared with 72.8±9.5 min, P<0.05). postoperative 2nd,3rd and 5th days, the MCPI group in VAS for pain at rest and Straight elevated leg were significantly lower than FNB group (P<0.05). The knee flexion of MCPI group was statistically greater than FNB group on the postoperative 3rd, and 5th days (P<0.05). Conclusions MCPI analgesia is better than FNB after total knee arthroplasty, which can shorten the operation time, and evidently prolong the Postoperative effective analgesia duration. Higher patient satisfaction is beneficial to early postoperative recovery. Trial registration: Chinese Clinical Trials Registry, ChiCTR1800020003,11/12/2018