Objective To observe and study the effect of neuromuscular exercise (NEMEX) on pain and physical function in patients with knee osteoarthritis (KOA). Methods From December 2016 to December 2017, a total of 70 participants with degenerative KOA were randomly divided into the control group and the observation group, with 35 participants in each group. The participants in the observation group received 8-weeks NEMEX, and the ones in the control group received 8-week quadriceps strengthening. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale and the WOMAC physical functional subscale were used to measure pain and physical function before treatment and after 1 week, 2 weeks, 4 weeks, and 8 weeks of treatment. Results The WOMAC pain scores of participants before treatment and after 1 week, 2 weeks, 4 weeks, and 8 weeks of treatment were 24.2±10.0, 23.4±9.1, 18.9±8.2, 15.0±6.3, 15.0±7.0, respectively in the observation group, and 25.6±9.8, 24.1±9.2, 20.2±8.8, 15.2±6.0, 11.4±5.3, respectively in the control group. After 1 week of treatment, neither group showed a significant change in pain than pretreatment (P>0.05), but after 2, 4, 8 weeks of treatment, both groups showed significant improvements in pain (P<0.05). There was no significant between-group difference in pain before treatment or after 1 week, 2 weeks, and 4 weeks of treatment (P>0.05), but after 8 weeks of treatment, statistically significant difference in WOMAC pain score was found between the two groups (t=2.439, P<0.05). The WOMAC physical function scores of participants before treatment and after 1 week, 2 weeks, 4 weeks, and 8 weeks of treatment were 94.3±31.0, 81.8±28.3, 68.9±22.1, 34.0±15.1, 22.0±8.0, respectively in the observation group, and 92.7±31.8, 82.6±29.3, 75.2±22.9, 52.2±20.0, 43.4±18.2 respectively in the control group. After 1 week, 2 weeks, 4 weeks and 8 weeks of treatment, both groups showed significant changes in WOMAC physical function scores than pretreatment (P<0.05). There was no statistically significant between-group difference before treatment or after 1, 2 weeks of treatment in physical function (P>0.05). The functional improvements in the observation group were significantly better than those in the control group after 4 and 8 weeks of treatment, and the differences were statistically significant (t=–4.287, –6.355; P<0.05). Conclusion NEMEX and quadriceps strengthening have similar effects in relieve pain in patients with KOA. And both exercises can effectively improve the physical function, and NEMEX is better than quadriceps strengthening on physical function improvement in patients with KOA.