The manzano pepper (Capsicum pubescens) is an exportation product that generates substantial earnings for local producers in Mexico. Herein we report on the most relevant metabolic changes that occur during the postharvest rot of manzano peppers caused by Fusarium temperatum. Simultaneously, we describe the effect of the Zanthoxylum limoncello leaf essential oil (ZlEO) and its major volatiles on the control of this devastating disease. According to our results, ZlEO, 2-undecanone (34%), 2-undecenal (32%), and 2-dodecenal (8%) exerted in vitro fungicide activity on F. temperatum (MIC, 104.6–218.3 mg L−1) and a strong in situ fungistatic effect in manzano peppers previously infected with F. temperatum. A differential fungistatic activity was observed for the natural agents assayed. However, the best results were confirmed with 2-dodecenal, which improved the shelf life of infected peppers up to 16 d post-inoculation. The protective effect of ZlEO and its major volatiles resulted in the conservation of fruit firmness, pH, protein, fat, fiber, ascorbic acid, and nutraceuticals of manzano peppers (carotenoids and capsaicinoids). Our findings endorse the potential use of ZlEO and its major volatiles as natural antifungals to prevent the soft rot triggered by F. temperatum.