Methylsulfonylmethane (MSM) is a food ingredient present in small amounts in many foods, and its anti-inflammatory effects have been reported. We conducted a randomized, double-blind, placebo-controlled trial of oral consumption of MSM on mild pain of the knee joint in healthy Japanese participants. A total of 88 participants were enrolled in this study and randomly assigned to MSM consumption ( = 44) and placebo control ( = 44) groups. Both groups of participants took 10 tablets, each containing 200 mg MSM or lactose, per day for 12 weeks. The primary outcome of this study was measured values of the total score of the Japanese Knee Osteoarthritis Measure (JKOM) at 12 weeks after the test sample consumption. Safety evaluation was performed through physical examination, urine analysis, peripheral blood test, and medical interview. The total scores at 12 weeks in the MSM and placebo groups as the primary outcome were significantly different ( = 0.046). The health condition of JKOM also improved after MSM consumption ( = 0.032). The questionnaire results also suggested improvement in the knee and systemic health. This study indicated that MSM oral consumption improved both knee and systemic health conditions in healthy participants who experienced mild pain in the knee joint.