Abstract: A series of ten chalcones (7a–j) and five new dihydrochromane–chalcone hybrids (7k–o) were synthesized and identified using spectroscopic techniques (IR, NMR, and MS). All compounds were evaluated in vitro against the B. cinerea and M. fructicola phytopathogens that affect a wide range of crops of commercial interest. All compounds were tested against both phytopathogens using the mycelial growth inhibition test, and it was found that two and five compounds had similar activity to that of the positive control for B. cinerea (7a = 43.9, 7c = 45.5, and Captan®= 24.8 µg/mL) and M. fructicola (7a = 48.5, 7d = 78.2, 7e = 56.1, 7f = 51.8, 7n = 63.2, and Mystic®= 21.6 µg/mL), respectively. To understand the key chalcone structural features for the antifungal activity on B. cinerea and M. fructicola, we developed structure–activity models with good statistical values (r2 and q2 higher than 0.8). For B. cinerea, the hydrogen bonding donor and acceptor and the atomic charge on C5 modulate the mycelial growth inhibition activity. In contrast, dipole moment and atomic charge on C1′ and the carbonyl carbon modify the inhibition activity for M. fructicola. These results allow the design of other compounds with activities superior to those of the compounds obtained in this study. Graphic Abstract: [Figure not available: see fulltext.].