The objective of this study was to determine the effect of dietary energy substrate and days on feed on apparent total tract digestibility, ruminal fermentation, short-chain fatty acid (SCFA) absorption, plasma glucose and acetate clearance rates, and insulin responsiveness. Eight ruminally cannulated, crossbred growing heifers were randomly allocated to 1 of 2 dietary treatments. The control (CON) diet consisted of 75.2% barley grain, 9.8% canola meal, 9% mineral and vitamin supplement, and 6% barley silage (DM basis). To evaluate the effect of energy source, a high-lipid, high-fiber byproduct pellet (HLHFP) was included in the diet by replacing 55% of the barley grain and 100% of canola meal. The study consisted of 4 consecutive 40-d periods (P1 to P4), with data and sample collection occurring in the last 12 d of each period. Dry matter intake tended ( = 0.10) to decrease by period and HLHFP-fed heifers tended to eat less ( = 0.09). The ADG of the CON was greater than that of the HLHFP during P1 and P4 (treatment × period, = 0.02). Heifers fed HLHFP tended to have greater mean ruminal pH (6.10 vs. 5.96; = 0.07) than heifers fed the CON, but pH was not affected by period. The CON heifers had a greater digestibility for DM, OM, CP, and NDF ( ≤ 0.03), and the digestibility for DM and OM linearly increased ( = 0.01) and for CP, NDF, and starch quadratically increased ( ≤ 0.04) with advancing period. Total SCFA concentration in the rumen was greater ( < 0.01) for the CON than for the HLHFP (141.6 vs. 128.1 m). The molar proportion of acetate and isobutyrate linearly increased and butyrate and valerate linearly decreased ( ≤ 0.05) with advancing periods. The rate of valerate absorption tended to increase (linear, = 0.06) and the ruminal liquid passage rate tended to decrease (linear, = 0.08) with advancing period. The arterial clearance rate of acetate tended to quadratically increase ( = 0.06) with period, whereas the clearance rate of glucose was not affected by treatment or period. Both fasting plasma insulin and the area under the insulin curve in response to glucose infusion linearly increased ( = 0.04) with period. These data suggest that partially replacing barley grain with HLHFP negatively affects total tract digestibility and performance. Moreover, with advancing days on feed, digestibility and insulin resistance increases without changes in ruminal pH and plasma metabolite clearance rates.