Kombucha is a functional beverage obtained through fermentation of sweetened Camellia sinensis infusion by a symbiotic culture of bacteria and yeasts that exerts many beneficial biological effects, mostly related to its antioxidant and anti-inflammatory effects. Alternative raw materials have been used to create new kombucha or kombucha-like products. Coffee is the most important food commodity worldwide and generates large amounts of by-products during harvest and post-harvest processing. The main coffee by-product is the dried fruit skin and pulp, popularly known as cascara. To date, no studies have evaluated the potential bioactivity of coffee cascara kombucha. In this study, we aimed to measure and compare the effects of infusions and kombuchas made with arabica coffee cascaras (n = 2) and black tea leaves (n = 1), fermented for 0, 3, 6, and 9 days on the intracellular production of Reactive Oxygen Species (ROS) and Nitric Oxide (NO) in model cells. Oxidative stress was induced in HK-2 cells with indoxyl sulfate (IS) and high glucose (G). Inflammation was induced with lipopolysaccharide (LPS) in RAW 264.7 macrophage. The contents of phenolic compounds, caffeine, and other physicochemical parameters were evaluated. To the best of our knowledge, this is the first study providing information on the bioactive profile and on the potential biological effects of coffee cascara kombucha. Fermentation caused the release of bound phenolic compounds from the infusions, especially total chlorogenic acids, with an average increase from 5.4 to 10.7 mg/100 mL (98%) and 2.6-3.4 mg/100 mL (30%) in coffee cascara and black tea kombucha, respectively, up to day 9. All evaluated beverages reduced (p < 0.0001) similarly the intracellular ROS (41% reduction, on average) and uric acid (10-55%) concentrations in HK-2 model cells, reversing the induced oxidative stress. All beverages also reduced (p < 0.0001, 81-90%) NO formation in LPS-induced macrophages, exhibiting an anti-inflammatory effect. These potential health benefits may be mostly attributed to polyphenols and caffeine, whose contents were comparable in all beverages. Coffee cascara showed similar potential to C. sinensis to produce healthy beverages and support sustainable coffee production.