The study investigated the effects of 48-h water and feed deprivation on blood and performance of grazing Nellore (Bos indicus) heifers. Twenty-four Nellore heifers (initial body weight [BW] = 238 ± 10 kg; age = 16 ± 2 mo), were ranked by initial BW and age and randomly assigned to 1 of 2 treatments: 1) grazing animals with free access to pasture, water, and mineral-mix (CON; n = 12), or 2) the same grazing conditions but deprived of pasture, water, and mineral-mix for 48 hours (DPR; n = 12). The paddocks consisted of Urochloa brizantha cv. Marandu, using a continuous and fixed stocking rate. The experiment lasted 225 days, with the first 14 days considered as the adaptation period (d -14 to -1) and the subsequent 211 days as the evaluation period (d 0 to 211). From day 0 to day 2, treatments were applied by keeping the DPR heifers in pens and reintegrating them into the experimental area after a 48-hour water and feed deprivation. Individual full BW was recorded on days -14, -13, -1, before (day 0) and after (day 2) treatment application, and on days 6, 11, 12, 41, 42, 210, and 211. Blood samples were collected in the morning on days 0, 2, 6, 12, and 211. A treatment effect was detected (P < 0.001) for shrink BW from day 0 to 2, which was greater (P < 0.001) in DPR vs. CON heifers. Subsequently, DPR animals were lighter (P < 0.001) compared with CON heifers by the end of the deprivation period (d 2). From day 4 to 211, DPR was lighter (P < 0.001) compared with CON heifers after treatment application and for the entire experimental period. In the first 10 days after treatment application (days 2 to 12), DPR heifers showed a partial compensatory ADG (P < 0.001) compared with CON heifers, while no significant differences were observed in ADG between the treatments from days 12 to 42 and 42 to 211 (P > 0.420). Overall ADG (days 2 to 211) was greater (P < 0.001) for DPR vs. CON heifers. All serum variables, except AST, were higher (P < 0.001) in DPR than in CON heifers on day 2 after treatment application. Our study demonstrates that grazing Nellore heifers subjected to 48-hour water and feed deprivation experienced significant alterations in their blood metabolites and BW immediately after the stressful event. Although the deprived heifers partially compensated for their body weight loss in the early days post-deprivation, they remained 12 kg lighter than the non-deprived animals throughout the production cycle.