The objective of the experiment was to investigate the effects of feeding a spray-dried plasma (SDP) product on production and blood profile in dairy cows during the transition and early lactation period. Seventy-two Holstein cows at 14 d before calving were used in a randomized block design. During the prepartum period, cows were fed a typical gestation diet containing blood meal (BM; 0.8% in dietary DM; Control, n = 24) or SDP (0.8% in dietary DM; n = 48). After calving, cows on control were fed a typical lactation diet containing 0.6% BM (DM basis). Cows on SDP prepartum were fed a lactation diet containing 0.6 (LowSDP; n = 24) or 2.4% SDP (HighSDP; n = 24) on a DM basis where SDP replaced BM or BM and soybean products. All data were analyzed using the MIXED procedure of SAS as a randomized block design. Prepartum supplementation of SDP had no effect on blood NEFA and BHBA (2 d before calving). After parturition, plasma NEFA (255 ± 29 µEq/mL) and BHBA (675 ± 70 µmol/L; 8 and 14 d of lactation) were not affected (P ≥ 0.61) by SDP in the diet. Cows fed SDP (Low and HighSDP vs. Control) did not affect DMI but increased or tended to increase (P ≤ 0.10) milk fat, protein, and lactose contents for 16 wks after parturition. High inclusion of SDP in the diet increased (P ≤ 0.07) milk yield (42 vs. 39 kg), ECM (44 vs. 41 kg), ECM per kg DMI, and yields of milk fat (1.60 vs. 1.48 kg/d), protein (1.21 vs. 1.16 kg/d), and lactose (2.07 vs. 1.97 kg) compared with LowSDP. Body weight losses were lower (P = 0.05) for SDP compared with the control without a difference between LowSDP and HighSDP. Plasma histidine concentration (d 14 of lactation) was lower (P = 0.01) for SDP compared with the control. In addition, plasma 1-methyl-L-histidine tended to be lower (P = 0.09) as inclusion rate of SDP increased. In conclusion, SDP at high inclusion rate increased milk and milk component yields without an increase in feed intake when blood meal was replaced in the diet. Studies evaluating effects of functional and active compounds in SDP on gut microbiome, gut health, and immune functions may be needed to determine mode of action.