New potential treatments for disseminated fungal infections are needed, especially for infections caused by the commonly drug-resistant pathogens Candida albicans and C. glabrata. These pathogens cause systemic candidiasis, a significant cause of mortality in immune-compromised patients. ABC transporters of the pleiotropic drug resistance subfamily, such as Cdr1p of C. albicans, play an important role in antifungal resistance and are potential bioassay targets for antifungal therapies against drug-resistant pathogens. We observed strong antifungal growth inhibitory activity in the methanol extract of Dalea formosa roots. This extract afforded six new isoflavonoids, sedonans A-F (1-6), a new but-2-enolide, 4'-O-methylpuerol A (7), and the new pterocarpan ent-sandwicensin (8). The structures and absolute configurations of these compounds were assigned using spectroscopic and chiroptical techniques. The direct antifungal activity of 1 against C. glabrata (MIC = 20 μM) was higher than that of fluconazole. Sedonans A-F and ent-sandwicensin were also active against Saccharomyces cerevisiae strains that express differing ABC transporter-associated resistance mechanisms but differed in their susceptibility to Cdr1p-mediated detoxification. A sedonan A (1)/ent-sandwicensin (8) combination exhibited synergistic growth inhibition. The results demonstrate that multiple crude extract compounds are differentially affected by efflux-mediated resistance and are collectively responsible for the observed bioactivity.