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Background: Chronic low-grade systemic inflammation is a characteristic of obesity that leads to various non-communicable diseases. Weight loss and SCFAs are potential strategies for attenuating obese systemic inflammation. Methods: Blood samples were collected from 43 obese subjects (BMI ≥ 30 kg/m²) scheduled for laparoscopic bariatric sleeve surgery, 26 obese subjects at follow-up 12–18 months post-surgery and 8 healthy weight subjects (BMI 18.5–24.9 kg/m²). Monocytes were isolated from blood and adipose tissue macrophages from visceral adipose tissue of obese subjects only. Isolated cells stimulated with 1 ng/mL LPS and treated simultaneously with 300 mM of sodium acetate or 30 mM of sodium propionate or butyrate and supernatant were harvested after 15 h incubation. TNF-α and IL-6 cytokines were measured via ELISA and mRNA gene expression of <i>FFAR2</i> and <i>FFAR3</i>, <i>HDAC1</i>, <i>HDAC2</i> and <i>HDAC9</i>, <i>RELA</i> and <i>NFKB1</i> and <i>MAPK1</i> via RT-qPCR. Results: TNF-α and IL-6 production and <i>NFKB1</i> and <i>RELA</i> mRNA expression were significantly decreased in follow-up subjects compared to baseline. SCFAs significantly reduced TNF-α and IL-6 and altered <i>FFAR</i> and <i>HDAC</i> mRNA expression in monocytes and macrophages from obese subjects. Conclusion: Weight loss and ex vivo SCFA treatments were successful in combatting systemic inflammation in obesity. Results highlighted molecular changes that occur with weight loss and as a result of SCFA treatment.