Milk fat depression (MFD) research has primarily focused on inhibitory effects of rumen biohydrogenation intermediates, particularly trans-10,cis-12 18:2 (CLA), on fat synthesis in the mammary gland. However, several studies have shown that directly increasing insulin-secretagogues through infusion also results in MFD. The objective of this meta-analysis was to evaluate the effects of glucose and propionate infusions on milk fat yield and energy balance. The analysis included 22 publications representing 27 glucose infusion treatments and 15 propionate infusion treatments. Trial-adjusted values were calculated in a linear mixed model with study included as a random variable and weighted by the inverse of the variance of daily milk yield. Trial-adjusted values for percent change in milk fat yield were regressed across levels of glucose (0.33 to 2.40 kg/d) and propionate (0.25 to 1.52 kg/d) infusion and lines of best fit were applied (r² = 0.76; r² = 0.65). Change in milk fat yield ranged from 1.69% to −20.3% for glucose infusions and from 6.78% to −23.8% for propionate infusions. Increasing glucose and propionate infusion amount increased the magnitude of MFD (P < 0.01; P < 0.01). Cows in each glucose infusion study were categorized as having high (HF; milk fat >4.09%), moderate (MF; milk fat ≥3.58% and ≤4.09%), or low (LF; milk fat <3.58%) milk fat concentrations. Increasing glucose infusion amount decreased milk fat yield of HF cows at a greater rate compared with LF cows (P = 0.03). MF cows also exhibited a greater response to glucose infusion compared with LF cows (P < 0.01). Trial-adjusted values for change in energy balance were regressed on percent change in milk fat yield following glucose infusion and a line of best fit was applied (r² = 0.74). Reducing milk fat yield from 1.69 to −20.3% through glucose infusion increased energy balance (−1.3 to 4.8 Mcal/d; P < 0.01). While CLA has been shown to cause MFD, the effects of insulin-secretagogues on energy partitioning should also be considered in the development of a comprehensive model.