Endotoxin administration is commonly used to study the inflammatory response, and though traditionally given as a bolus injection, it can be administered as a continuous infusion over multiple hours. Several studies hypothesize that the latter better represents the prolonged and pronounced inflammation observed in conditions like sepsis. Yet very few experimental studies have administered endotoxin using both strategies, leaving significant gaps in determining the underlying mechanisms responsible for their differing immune responses. We used mathematical modelling to analyse cytokine data from two studies administering a 2 ng kg−1 dose of endotoxin, one as a bolus and the other as a continuous infusion over 4 h. Using our model, we simulated the dynamics of mean and subject‐specific cytokine responses as well as the response to long‐term endotoxin administration. Cytokine measurements revealed that the bolus injection led to significantly higher peaks for interleukin (IL)‐8, while IL‐10 reaches higher peaks during continuous administration. Moreover, the peak timing of all measured cytokines occurred later with continuous infusion. We identified three model parameters that significantly differed between the two administration methods. Monocyte activation of IL‐10 was greater during the continuous infusion, while tumour necrosis factor α$ {\alpha} $ and IL‐8 recovery rates were faster for the bolus injection. This suggests that a continuous infusion elicits a stronger, longer‐lasting systemic reaction through increased stimulation of monocyte anti‐inflammatory mediator production and decreased recovery of pro‐inflammatory catalysts. Furthermore, the continuous infusion model exhibited prolonged inflammation with recurrent peaks resolving within 2 days during long‐term (20–32 h) endotoxin administration. What is the central question of this study?How do dynamic immune responses to continuous and bolus endotoxin administration compare using mathematical models, and what physiological mechanisms do we hypothesize attribute to these observed differences? How do extended and enhanced continuous infusions impact immune responses, and do they express similar characteristics to infection dynamics?What is the main finding and its importance?This study proposes a mathematical model for a continuous infusion of endotoxin. We hypothesize that the dynamic switch from a bolus to a continuous infusion of endotoxin, which results in higher peak concentrations of IL‐10, lower peak concentrations of IL‐8, and later peak timing of all measured cytokines, is attributed to increased monocyte activation rate of anti‐inflammatory cytokine IL‐10 and decreased decay rates of pro‐inflammatory cytokines TNF‐a and IL‐8. Additionally, prolonged LPS administration significantly extends the cytokine response and results in recurrent cytokine spikes. Our results provide a better understanding of the mechanisms impacting the change in immune responses with long‐term endotoxin infusion. [ABSTRACT FROM AUTHOR]