This paper presents the discovery and development of antifungal agents against Fusarium oxysporum (Fox), a devastating plant pathogen. Diethyl 2-((arylamino)methylene)malonates (DAMMs) were formed as side-products during the synthesis of polysubstituted-2-pyridones through a three-component domino reaction and seemed to have antifungal activity against Fox. DAMMs are typically employed as intermediates or precursors to produce further bioactive compounds, but they have never been examined as antifungals. To confirm this latter characteristic, we employed a single-step procedure (i.e., the first step of the Gould-Jacobs reaction) to prepare five DAMMs (74–96% yields) which were subsequently evaluated against Fox in terms of their abilities to inhibit mycelial growth. The antifungal outcome was promising (0.013 µM < IC50 < 35 µM), involving fungistatic or fungicide effects. This small group of active compounds showed differences in antifungal activity, constituting the basis of further studies to expand the DAMM chemical space and look for improved antifungal activity.