In our continuing efforts to discover novel triazoles with improved antifungal activity in vitro and in vivo, a series of 41 novel compounds containing 1,2,3-triazole side chains were designed and synthesized via a click reaction based on our previous work. Most of the compounds showed moderate to excellent broad-spectrum antifungal activity in vitro. Among them, the most promising compound <b>9A</b><sub><b>16</b></sub> displayed excellent antifungal and anti-drug-resistant fungal ability (MIC<sub>80</sub> = 0.0156-8 μg/mL). In addition, compound <b>9A</b><sub><b>16</b></sub> showed powerful in vivo efficacy on mice systematically infected with <i>Candida albicans</i> SC5314, <i>Cryptococcus neoformans</i> H99, fluconazole-resistant <i>C. albicans</i> 100, and <i>Aspergillus fumigatus</i> 7544. Moreover, compared to fluconazole, compound <b>9A</b><sub><b>16</b></sub> showed better in vitro anti-biofilm activity and was more difficult to induce drug resistance in a 1 month induction of resistance assay in <i>C. albicans</i>. With favorable pharmacokinetics, an acceptable safety profile, and high potency in vitro and in vivo, compound <b>9A</b><sub><b>16</b></sub> is currently under preclinical investigation.