The overexploitation of wild plants for medicinal uses and conventional agricultural farming methods, which use high amounts of water, fertilizers, and pesticides, have had devastating environmental consequences. This study aimed to evaluate the prospects of using aquaponics and hydroponics as alternative approaches to soil cultivation by comparing the crop yields, secondary metabolite contents, and the antifungal activities of ethanol extracts of Helichrysum odoratissimum (L.) Sweet, a widely used medicinal plant species in Southern Africa. Six-week-old H. odoratissimum seedlings were grown in aquaponic and hydroponic systems. The growth parameters, secondary metabolite contents, and antifungal activity against Fusarium oxysporum were assessed. The results for crop yield (plant height, fresh and dry weights) and the tissue nutrient contents did not change substantially (p > 0.05) between aquaponic and hydroponic treatments. Gas chromatography–mass spectrometry (GC–MS) analysis showed that monoterpenes and sesquiterpenes were the most abundant compounds in H. odoratissimum; however, no statistical difference was observed among the field, hydroponic, and aquaponic plants (DF = 2; χ² = 2.67; p > 0.05). While there was no significant difference in polyphenol contents among the three treatments, remarkably, the flavonol contents in the leaves varied significantly (DF = 2; χ² = 6.23; p < 0.05) among the three treatments. A higher flavonol content occurred in leaves from the hydroponic system than in leaves from the aquaponic (p < 0.05) and field (p > 0.05) systems. The MIC results showed that the ethanolic extract of H. odoratissimum was fungistatic against F. oxysporum; however, this effect was more prominent in the ethanol extracts of plants grown in the aquaponic system, with a mean MIC value of 0.37 ± 0.00 mg/mL The key findings of this study are that aquaponically cultivated plants exhibited the best antifungal activity, while higher total flavonol contents occurred in the hydroponically cultivated plants. In conclusion, aquaponics and hydroponics performed better or similar to field cultivation and are viable alternative methods for cultivating H. odoratissimum plants.