The increasing energy required to synthesize inorganic fertilizers warrants more sustainable soil amendments that produce comparable crop yields with less environmental damage. Duckweed, a prolific aquatic plant, can not only sequester carbon dioxide through photosynthesis, but also hyperaccumulate nutrients from its environment and upcycle them into valuable bioproducts. In this study, dried duckweed, grown on treated wastewater treatment plant effluent, was utilized as a fertilizer for a variety of crops (beet, tomato, kale, and sorghum). Comparative experiments examined the effect of duckweed, inorganic fertilizer, and a 40–60 mix of both on crop yield and nutrient fate in the plants, soil, and leachate. Comparable yields of beet, tomato, and sorghum were generated with duckweed and inorganic fertilizer. Duckweed significantly enhanced phosphorus (P) uptake in sorghum, exhibiting a P use efficiency level of 18.48%, while the mix treatment resulted in the highest P use efficiencies in beet and tomato. Duckweed-amended beet and kale systems also increased residual soil N (0.9% and 11.1%, respectively) and carbon (4.5% and 16.6%, respectively). Linear regression models developed using the data collected from all crops confirmed that duckweed can be used as a substitute for inorganic fertilizer without negative effects to food yield or nutritional quality.