Flavonoids have shown health-benefiting properties, such as antioxidative and anti-inflammatory activities, and are commonly used as nutraceuticals and pharmaceuticals. Although flavonoids are predominantly identified from plants, several filamentous fungal species have also been reported to produce bioactive flavonoids, including chlorflavonin from Aspergillus candidus, a novel halogenated flavonoid with potent antifungal and antitubercular (anti-TB) activities. Unfortunately, the low water-solubility of this molecule may hinder its bioavailability. Glycosylation is an effective method to enhance the polarity of natural products and alter their physicochemical properties. This work focuses on the development of novel water-soluble chlorflavonin derivatives to combat the threat of drug-resistant tuberculosis. In this study, we first increased the production titer of chlorflavonin in A. candidus NRRL 5214 by optimizing the fermentation and purification processes. Next, chlorflavonin-5-O-β-d-glucuronopyranoside (1) and chlorflavonin-7-O-4″-O-methyl-β-d-glucopyranoside (2) were produced from chlorflavonin using Streptomyces chromofuscus ATCC 49982 and Beauveria bassiana ATCC 7159, respectively. Compared to chlorflavonin (4.38 ± 0.54 mg/L in water), the water solubility of the two new glycosides was determined to be 117.86 ± 4.81 mg/L (1) and 124.34 ± 9.13 mg/L (2), respectively. This study provides a promising method to create water-soluble glycosides of chlorflavonin for the development of novel anti-TB drugs.