Candida species are normally commensal yeasts residing in the human body, under certain circumstances, can trigger pathological conditions such as candidiasis, not to mention antifungal resistance. Lippia sidoides Cham., or pepper-rosmarinus, is a native plant found in the Northeastern semi-arid region of Brazil, cited in ethnobotanical studies for its bioactive potential. This approach aims not only to expand the understanding of the antifungal efficacy of the ethanol extract of L. sidoides (EELs) but also to evaluate synergies that may enhance the available therapeutic arsenal, using the checkerboard method, and to assess potential toxic effects of this extract using model organisms, Artemia salina and Drosophila melanogaster, to evaluate mortality rates. Antifungal activity was observed at high concentrations (>1024 μg/mL) for both strains of Candida albicans and Candida krusei tested, with the most significant inhibition of fungal growth when the compound was used in synergy with fluconazole at 8.0 and 128 μg/mL, respectively. This activity likely occurred due to the interaction between the chemical composition of the ethanol extract rich in flavonoids and tannins with the reference drug. Regarding toxicity, both in relation to D. melanogaster and A. salina, no toxic results were observed at low concentrations. These results suggest that the ethanol extract of EELs may be a potential alternative as an adjuvant to fluconazole in the treatment of fungal infections caused by Candida spp. The observed synergy suggests that this combination may help overcome resistance to conventional antifungals and improve treatment efficacy.