Modern hydroponic substrates have contributed significantly to the popularity and progress of hydroponic cultivations worldwide, nevertheless, their development, transportation, and disposal often come at a significant environmental cost. Here we investigate the feasibility of partial to total replacement of conventional organic growing media constituents, such as cocodust (C), in a 20% perlite (P) and 80% cocodust substrate (hereafter control 8C), with compost from locally sourced grocery waste (W). For this purpose, four treatment mixtures were developed (6C:2W, 4C:4W, 2C:6W, 8W), with the grocery waste-compost fraction ranging from 20 to 80%, respectively (perlite constant at 20%). The new substrates were tested on hydroponic lettuce (Lactuca sativa var. Tanius) cultivation. During the 35-day experiment, lettuce physiology was evaluated using chlorophyll concentration [SPAD], chlorophyll fluorescence [Fv/Fm], number of leaves, and plant growth index. At harvest, the plant yield was evaluated using leaf area [cm2], leaf fresh and dry weight [g], as well as leaf firmness [g]. Results show that substrates with compost led to superior physiology and yield characteristics, with 8W inducing a significant increase in leaf area, chlorophyll concentration, dry weight, and firmness, by 11.6%, 5.4%, 19.8% and 12.8%, respectively, compared to the control treatment 8C. Results indicate that grocery waste-based compost is an excellent sustainable alternative for the soilless cultivation of lettuce. After its use in hydroponic cultivation, substrate material is safe to dispose of or be used as a soil amendment, thus contributing to a circular agro-food economy model.