Partial least square regression estimates of milk and blood constituents using Fourier transform mid-infrared (FTIR) analysis have shown promise as a tool for monitoring early lactation excessive energy deficit in dairy herds. Our objective was to analyze milk via mid-FTIR to determine the association of early lactation predicted milk β-hydroxybutyrate (BHB) concentrations, predicted blood nonesterified fatty acid (NEFA) concentrations, and predicted milk de novo fatty acid (FA) percentages relative to total FA concentrations with the risk of negative outcome diagnosis (hyperketonemia, displaced abomasum, metritis, culling, and/or death). We enrolled 517 multiparous Holstein cows from 2 dairy farms in New York State. Proportional, composite milk samples were collected twice weekly from 3 to 18 DIM for a total of 4 time points (T1: 3 to 7 DIM; T2: 6 to 11 DIM; T3: 10 to 14 DIM; T4: 13 to 18 DIM) and analyzed using mid-FTIR spectrometry for milk BHB and FA composition and predicted blood NEFA. Blood samples were collected for hyperketonemia determination (blood BHB ≥ 1.2 mmol/L) using a hand-held meter within 1h of milk sample collection, and farm-diagnosed occurrence of negative outcomes during the first 30 DIM was collected from herd management software. The incidence of negative outcomes between 3 and 18 DIM was 20.2%. Explanatory models were developed for each predicted milk constituent of interest at each time point using fixed effect multivariable Poisson regression for negative outcome prediction. For all time points, an increased risk of negative outcome diagnosis was associated with higher predicted milk BHB (Relative Risk (RR)_T1 = 2.0; RR_T2 = 3.4; RR_T3 = 5.2; RR_T4 = 9.1; all P ≤ 0.002), higher predicted blood NEFA (RR_T1 = 2.7; RR_T2 = 2.5; RR_T3 = 3.8; RR_T4 = 10.0; all P ≤ 0.001), and lower predicted milk de novo FA relative percentages (RR_T1 = 2.9; RR_T2 = 3.3; RR_T3 = 5.8; RR_T4 = 7.2; all P ≤ 0.001). Our results suggest that mid-FTIR predicted milk BHB, blood NEFA, and milk de novo FA relative percentages are promising indicators of subsequent negative outcome diagnosis in early lactation.