《达·芬奇的恶魔》被定位为冒险故事，聚焦在文艺复兴时期达·芬奇在佛罗伦萨的青年时代，融合了各种真实和戏说的历史故事。其中情节曲折惊险，描叙了各种冒险故事。
奥斯奥军队即将挥军意大利，对此兵临城下的威胁，教皇遇到比这更大的麻烦。温妮莎得到尼克的帮助，命运也出现了极大的改变，佛罗伦萨新管治层变天。
达芬奇返回佛罗伦萨，发现佛罗伦萨已落入伯爵手中，佛罗伦萨再不是从前的佛罗伦萨,在伯爵铁腕管治下，佛罗伦萨沦为地狱，达芬奇将面对前所未见的敌人。而已落入手中。利拉奥醒觉到要为自己所作过的罪业赎罪。
达芬奇和利拉奥双双被困，正要面临死亡威胁，Zoroaster和尼克计划着逃离的方法。卢奎西娅打算会见那不勒斯国王和来到罗马的特使，希望从二人口中打探出教皇的阴谋。
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