Our aim was to determine effects of two S. cerevisiae yeast based direct fed microbial (DFM) feed additives on the productive response of high producing early lactation dairy cows. The study consisted of three high producing Holstein cow pens (± 315 cows/pen) in a 3 × 3 Latin square design experiment with 3 periods of 28 d each. The 3 treatments were: (1) Basal total mixed ration (Control), (2) Control supplemented with ‘XPC’ yeast culture at 14 g/cow/d and, (3) Control supplemented with ‘Yeasture (YST)’ DFM at 10 g/cow/d. Milk (P = 0.01), milk true protein (P = 0.01), lactose (P = 0.01) and energy (P = 0.02) outputs were higher for YST cows, and there was a tendency for milk fat (P = 0.07) to increase compared to Control cows. In contrast, milk and component yields were not impacted by feeding XPC. Total net energy (NE) output was higher for both DFM treatments vs. Control (YST (P < 0.01) and XPC (P = 0.01)), but neither treatment impacted the NE level of the diets. Total tract apparent digestibility of organic matter (OM) and crude protein (CP) tended to be lower (P = 0.08 and 0.05) than Control for the XPC treatment, while total tract apparent digestibility of OM and CP for YST cows was lower (P = 0.02 and < 0.01 respectively) than Control. Total tract apparent digestibility of ash-free neutral detergent fibre (aNDFom) and starch were not affected by treatment, and there was no effect of either DFM treatment on microbial CP (MCP) flow from the rumen. Total plasma essential amino acid (EAA) concentrations tended to be higher (P = 0.07) with YST, which was mainly driven by increases in threonine (P = 0.03), tryptophan (P = 0.02), valine (P = 0.08) and histidine (P = 0.06). Although total plasma non-essential amino acids (NEAA) did not differ with YST feeding, there was an increase in concentrations of glycine (P = 0.04), asparagine (P = 0.03), tyrosine (P = 0.05), serine (P = 0.07), proline (P = 0.06) and taurine (P = 0.07). In contrast, XPC had no impact on plasma concentrations of any AA. Overall, MCP flow and whole tract aNDFom data suggest no substantive impact of either yeast additive on rumen fermentation, but whole tract digestibility of OM and plasma AA concentrations suggest a post-ruminal effect of YST wherein gut health improved thereby leading to increased efficiency of nutrient absorption.