Obesity-associated adipose tissue remodeling, including adipocyte hypertrophy, contributes to a chronic state of low-grade inflammation that promotes breast cancer growth through multiple signaling pathways. Inflammation is often regulated and perpetuated by epigenetic modifications, including aberrant DNA methylation. However, the precise relationship between obesity-associated inflammation, epigenetic modifications and breast cancer has not been clearly elucidated. Furthermore, the plasticity of obesity-associated DNA methylation and impact on tumor growth after weight loss remains unclear. We hypothesized that targeting obesity-associated inflammation would be critical to reduce mammary tumor growth. We found that anti-inflammatory supplementation (Resveratrol or Sulindac) in obese mice reduced mammary tumor growth in association with decreased adipocyte size, influx of macrophages, and expression of pro-inflammatory mediators in the mammary tissue. We then tested if obesity-associated inflammation was reversible with weight loss by low-fat diet (LFD) and found that the pro-tumorigenic effects of obesity and aberrant methylation of inflammatory genes persists after weight loss. Considering the substantial evidence demonstrating that weight loss via bariatric surgery reduces cancer risk, we established a surgical sleeve gastrectomy (SG) protocol in our mouse model of obesity. We demonstrated that weight loss via surgery and LFD was equally effective at reducing body weight, but produced differential effects on tumor growth and systemic inflammation. Mice that lost weight via SG, but not LFD alone, had reduced tumor growth compared to obese mice. Additionally, mice that received SG had more effectively reversed expression of pro-inflammatory mediators and aberrant DNA methylation of metabolism related genes observed in obese mice. Our results that 1) targeting inflammation reduces mammary tumor growth in obese mice; 2) pro-inflammatory gene expression and aberrant methylation of inflammatory-related genes persists after weight loss by diet; 3) weight loss via surgery, but not LFD, significantly reduces tumor growth and more effectively reverses obesity-induced aberrant methylation. We have identified the critical mechanisms underlying the protective effects of anti-inflammatory supplementation or bariatric surgery as preventing adipocyte hypertrophy and macrophage infiltration, decreasing expression of pro-inflammatory mediators, and normalizing DNA methylation in the mammary tissue. These results could inform the development of mechanism-based strategies to more precisely intervene to prevent obesity-related cancers.