Background Sepsis is associated with dynamic metabolic alterations influencing energy expenditure and substrate utilization. This study aimed to evaluate time-course changes in energy metabolism in critically ill patients with sepsis and identify clinical and nutritional predictors of resting energy expenditure (REE) and respiratory quotient (RQ). Methods In this prospective observational study, 30 mechanically ventilated adult patients with sepsis were assessed using indirect calorimetry on days 1, 2, 3, 5, and 7 following diagnosis. Nutritional treatment, biochemical markers, and clinical variables were recorded. Linear mixed-effects models were applied to evaluate temporal changes and identify predictors of REE and RQ. Results REE increased by Day 5 versus Day 1 (+ 163.7 kcal/day; p = 0.049), with a concurrent rise in RQ (p = 0.013). Higher body temperature, higher arterial pH, a greater protein-to-non-protein calorie ratio, and higher protein intake were associated with higher REE, whereas higher lactate concentrations and use of CRRT were associated with lower REE. RQ was positively associated with energy intake, REE coverage, and blood glucose. Clinical-severity scores and inflammatory markers showed no significant associations with REE or RQ. Conclusions Energy metabolism in sepsis evolves dynamically, with significant changes in REE and substrate utilization over time. Temperature, acid-base balance, CRRT, and nutritional strategies were associated with variability in energy expenditure. These findings support the need for individualised metabolic assessment and targeted nutritional strategies in critically ill patients with sepsis.