Chronic inflammation involves dysregulation in the synthesis of pro-inflammatory mediators which are associated with several diseases such as obesity and diabetes. Some nutraceuticals are known to possess anti-inflammatory properties based on their high content of phytochemicals and fibres. We have previously demonstrated that ethanol extracts of whole dried sugarcane (WDS) regulate the expression of crucial inflammatory mediators in vitro in an LPS induced colon cancer cell model. In the current study, we evaluated the effects of WDS in a high fat (HF)-fed mouse model by employing multiplex ELISA and SWATH-based proteomics studies to examine cytokines and liver protein expression, respectively. Benefiber® (BF), a commercially available food supplement, was also examined as an alternative fibre source. Dietary supplementation using either WDS or BF produced any significant shifts in pre-diabetic markers such as weight gain or glucose tolerance tests. Inflammatory and diabetes markers in plasma were not altered in the presence of these supplements. However, protein expression from 2,388 proteins quantified across 40 samples in liver tissue showed that WDS significantly repressed the inflammatory modulator STAT3 and the selenium-associated proteins SEP15 and SECS compared to the HF group, events not observed after BF supplementation. Ingenuity Pathway analysis from this data predicted WDS would repress hepatic functions such as incidence of liver tumour, fibrosis of liver, and liver metastasis. These results suggest that the nutraceutical properties of WDS might be useful in modulating inflammatory properties of the liver and warrant exploration in other disease models.