Wheat is the third most cultivated cereal in the world and represents the major contributor to human nutrition. Milling wheat by-products such as husks (17–20% of the total processing output weight), even if still containing high-value-added bioactive compounds, are often left untreated or unused, thus resulting in environmental and human health burdens. In these regards, the present study is aimed at evaluating in a multimethodological approach the nutraceutical properties of durum wheat husks belonging to the ancient cultivar “Senatore Cappelli”, thus assessing their potential as bioactive compound sources in terms of phytochemical, cytotoxic, and nutraceutical properties. By means of HPLC-FD analyses, wheat husk samples analyzed revealed a higher content of serotonin, amounting to 35% of the total BAs, and were confirmed to occur at biogenic amines quality index (BAQI) values <10 mg/100 g. In addition, spectrophotometric assays showed a significant variable content in the phenolic (189.71–351.14 mg GAE/100 g) and antioxidant compounds (31.23–37.84 mg TE/100 g) within the wheat husk samples analyzed, according to the different cultivar areas of origin. Considering wheat husk extracts’ anti-inflammatory and antioxidant activity, in vitro analyses were performed on BV-2 murine microglia cells cultured in the presence or absence of LPS, thus evaluating their ability to promote microglia polarization towards an anti-inflammatory phenotype. Cytotoxicity assays showed that wheat extracts do not affect microglia viability. Wheat husks activity on microglial polarization was assessed by analyzing the expression of M1 and M2 markers’ mRNA by RT-PCR. Wheat husk antioxidant activity was assessed by analysis of NRF2 and SOD1 mRNA expression. Moreover, the sustainability assessment for the recovery of bioactive components from wheat by-products was carried out by applying the life cycle assessment (LCA) methodology using SimaPro v9.2.2. software.