This study evaluated the in vitro interaction between ciprofloxacin (CIP) and classical antifungals against Histoplasma capsulatum var. capsulatum in mycelial (n = 16) and yeast-like forms (n = 9) and Coccidioides posadasii in mycelial form (n = 16). This research was conducted through broth microdilution and macrodilution, according to Clinical Laboratory Standards Institute. Inocula were prepared to obtain from 0.5 × 103 to 2.5 × 104 cfu ml−1 for H. capsulatum and from 103 to 5 × 103 cfu ml−1 for C. posadasii. Initially, minimum inhibitory concentration (MIC) for each drug alone was determined. Then, these MICs were used as the highest concentration for each drug during combination assays. The procedures were performed in duplicate. For all combination assays, MICs were defined as the lowest concentration capable of inhibiting 80% of visible fungal growth, when compared to the drug-free control. Drug interaction was evaluated by paired sample t-Student test. The obtained data showed a significant MIC reduction for most tested combinations of CIP with antifungals, except for that of CIP and voriconazole against yeast-like H. capsulatum. This study brings potential alternatives for the treatment of histoplasmosis and coccidioidomycosis, raising the possibility of using CIP as an adjuvant antifungal therapy, providing perspectives to delineate in vivo studies.