The aim of this study was to evaluate the effect of replacing Tifton-85 hay (Cynodon spp. cv. Tifton 85) with 0, 150, 300, 450 and 600 g/kg dry matter (DM) of spineless cactus (SC, Nopalea cochenilifera Salm-Dyck) plus urea and ammonium sulfate (UAS; 9:1) on DM, digestible organic matter (DOM) and indigestible neutral detergent fiber (iNDF) intakes, as well as ruminal fermentation, N-balance, and microbial protein supply (MPS). Five rumen-fistulated and cannulated crossbred wethers, weighing 43.8 ± 5.80 kg, were randomized in a 5 × 5 Latin square design. Isonitrogenous diets (14% crude protein) were supplied with a roughage/concentrate ratio of 70:30. The DOM intake, N-retained, and MPS showed quadratic responses (p < 0.05), with maximum values estimated at the levels of SC+UAS of 414, 438 and 418 g/kg DM, respectively. Rumen pH and ammonia nitrogen, iNDF intake, N-urinary excretion, and serum urea and plasma ammonia reduced linearly (p < 0.05) with increasing SC+UAS inclusion. Ruminal acetate and propionate concentrations increased linearly with increasing SC+UAS inclusion. In wethers fed diets with a roughage/concentrate ratio of 70:30, roughage constituted of a SC+UAS/hay (Tifton-85) ratio of 41:29 is recommended in order to maximize the DOM intake, N-retention, and MPS.