Interventions to decrease inflammation and improve metabolic function hold promise for the prevention of obesity-related diseases. Methylsulfonylmethane (MSM) is a naturally occurring compound that demonstrates antioxidant and anti-inflammatory effects. Improvements in measures of metabolic health have been observed in mouse models of obesity and diabetes following MSM treatment. However, the effects of MSM on obesity-related diseases in humans have not been investigated. Therefore, the purpose of this investigation was to determine whether MSM supplementation improves cardiometabolic health, and markers of inflammation and oxidative status. A randomized, double-blind, placebo-controlled design was utilized with a total of 22 overweight or obese adults completing the study. Participants received either a placebo (white rice flour) or 3 g MSM daily for 16 weeks. Measurements occurred at baseline and after 4, 8, and 16 weeks. Outcome measures included fasting glucose, insulin, blood lipids, blood pressure, body composition, metabolic rate, and markers of inflammation and oxidative status. The primary finding of this work shows that high-density lipoprotein cholesterol was elevated at 8 and 16 weeks of daily MSM consumption compared to baseline, (p = 0.008, p = 0.013). Our findings indicate that MSM supplementation may improve the cholesterol profile by resulting in higher levels of high-density lipoprotein cholesterol.