The efficiency of cognition is modulated by energetic factors like effort, fatigue or circadian variation, which affect even the most basic cognitive operations. For instance, speeded detection in simple reaction-time (SRT) tasks usually slows down over time. The literature suggests that either mindlessness due to routinization or mental fatigue due to attentional resource depletion might underlie this decrement. We tested these assumptions in three 25-min visual SRT tasks using easy-to-detect high-intensity and hard-to-detect low-intensity stimuli presented in both blocked and mixed fashion. Mindlessness theory predicts that less monotonous stimulation (i.e. the mixed presentation) would mitigate the time-related decrement for high- and low-intensity stimuli alike, whereas resource-depletion theory predicts opposite effects of mixed presentation on high- versus low-intensity stimuli. Indeed, stimulus intensity and presentation mode cross-interacted significantly, indicating that the performance decline was steeper for high-intensity stimuli but less steep for low-intensity stimuli during mixed compared to blocked presentation, respectively. These results strongly suggest that the time-related efficiency decrement during prolonged SRT performance is related to accumulating mental fatigue. A conjecture is put forward that explains both resource depletion and mindlessness from the perspective of self-regulation. Our study underscores the need to incorporate energetic factors into models of cognition to facilitate their translation into real-world applications.