The extensive use of fluconazole (FLC) and other azole drugs has caused the emergence and rise of azole-resistant fungi. The fungistatic nature of FLC in combination with toxicity concerns have resulted in an increased demand for new azole antifungal agents. Herein, we report the synthesis and antifungal activity of novel alkylated piperazines and alkylated piperazine-azole hybrids, their time-kill studies, their hemolytic activity against murine erythrocytes, as well as their cytotoxicity against mammalian cells. Many of these molecules exhibited broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against non-albicans Candida and Aspergillus strains. The most promising compounds were found to be less hemolytic than the FDA-approved antifungal agent voriconazole (VOR). Finally, we demonstrate that the synthetic alkylated piperazine-azole hybrids do not function by fungal membrane disruption, but instead by disruption of the ergosterol biosynthetic pathway via inhibition of the 14α-demethylase enzyme present in fungal cells.