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<i>Citrus</i> fruits are often employed as ingredients for functional drinks. Among <i>Citrus</i>, the variety, &#8220;Lempso&#8222;, a typical hybrid of the Calabria region (Southern Italy), has been reported to possess superior antioxidant activity when compared to other common <i>Citrus</i> varieties. For these reasons, the aim of this study is to investigate in vitro the nutraceutical value of the Tarocco clone, &#8220;Lempso&#8222;, highlighting its anti-inflammatory and antioxidant potential. A post-column 2,2&#8242;-diphenyl-1-picrylhydrazyl (DPPH&#8226;) radical scavenging assay for the screening of antioxidant compounds in these complex matrices was developed. Subsequently, polyphenolic extract was tested on a murine macrophage cell line under inflammatory conditions. The extract resulted was able to significantly inhibit nitric oxide (NO) and cytokine release and inducible nitric oxide synthase (iNOS) and cycloxygenase-2 (COX-2) expression. The inhibition of these pro-inflammatory factors was associated to Nuclear factor-kB (NF-kB) inhibition. Our results also indicate an anti-oxidant potential of the extract as evidenced by the inhibition of reactive oxygen species (ROS) release and by the activation of the nuclear factor E2-related factor-2 (Nrf-2) pathway in macrophages. The obtained results highlight the anti-inflammatory and antioxidant potential of Lempso extract and its potential use, as a new ingredient for the formulation of functional beverages with high nutraceutical value, providing health benefits to consumers.