The use of peat, the standard substrate used for soilless cultivation of horticultural crops, is becoming of increasing concern as peat is a non-renewable resource and its extraction can degrade wetland ecosystems, creating a strong environmental impact. For this reason, the search for organic materials that can totally or partially replace peat has become increasingly important. In this research, three types of composts (C1, C2, C3), derived from cardoon biomass mixed in different volumes with woody and/or fruit wastes, were utilized as the constituents of growing media, at two dilution rates with peat (60:40 and 30:70 v:v), to assess their effect on the growth and quality of baby leaf lettuce in a greenhouse trial. The two cultivars Imperiale and Verde d’Inverno, belonging to the butterhead and romaine lettuce types, respectively, were employed. Plant performance and yield were unaffected or were positively affected by compost-containing growing medium compared to the control. The cultivars responded differently to the growing medium; the Imperiale showed the highest yield with C1 compost at a 60% rate while the Verde d’Inverno with the C2 was at 30%. The total chlorophyll, carotenoids, and ascorbic acid were found higher in the Verde d’Inverno than in the Imperiale variety while the total polyphenols, flavonoids, and antioxidant activity were lower. Also, the content of chlorophylls as well as of antioxidant compounds and antioxidant activity were differently affected by the growing medium, depending on the lettuce cultivar. The results obtained indicate that cultivated cardoon waste-based compost is a promising constituent of the growing media for baby leaf production. The specific varietal response observed should be considered to optimize both yield and product quality.