Objective: To investigate the differences of clinical efficacy and serum levels of β-endorphins among the verum acupuncture, non-acupoint acupuncture and celecoxib on knee osteoarthritis (KOA) patients. Methods: From September 2017 to September 2019, 108 KOA patients were recruited in this trial and randomly divided into three groups: verum acupuncture (VA) group, non-acupoint acupuncture (NA) group and celecoxib group. In VA group, patients accepted acupuncture at Yanglingquan (GB34), Yinlingquan (SP9), two Ashi points around the knees, if no ashi points existed, Dubi (ST35) and Neixiyan (EX-LE4) would be chose. In NA group, patients accepted acupuncture at four non-acupoints around the knees. Acupuncture treatment was performed once per day, five times per week, and 10 sessions totally. In celecoxib group, patients accepted oral celecoxib 200mg per day for two weeks. The Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis index (WOMAC), Self-rating Anxiety Scale (SAS), Self-rating Depression Scale (SDS) serum level of beta-endorphin (β-EP) were assessed before and after the treatments. Results: Within group comparison: The VAS, WOMAC, pain and functional subscale in WOMAC of the three group were significantly decreased after treatment when compared with baseline (P<0.01). The stiffness subscale in WOMAC, SAS and SDS in VA group were significantly improved after treatment (P<0.01). In NA group, the SDS (P<0.01), stiffness subscale in WOMAC and SAS (P<0.05) after treatment were significant improved. In celecoxib group, the stiffness subscale in WOMAC and SAS were decreased significantly after treatments (P<0.01). Between group comparison: The VAS, WOMAC and three subscales, SAS, SDS in three groups after treatment showed no statistical difference (P>0.05). The change of VAS in celecoxib group and NA group after treatment had significant difference (P<0.05). Serum level of β-EP: The serum level of β-EP of KOA patients in VA group aftertreatment was significant decreased (P<0.001). In celecoxib group, the β-EP level was also decreased after treatment (P<0.05). The changes of β-EP level between VA group and NA group were significant different (P<0.01). Conclusions: VA can improve the pain, function, and serum β-EP level of KOA patients.