This study aims to determine the significant factors that affect the mental fatigue of construction workers in the Philippines. Studies revealed that workers in the construction site routinely exceed generally accepted physiological thresholds for manual work leading to fatigue. They typically carry out highly demanding physical tasks with various types of stresses resulted from awkward posture, excessive force demands, repetitive actions and excessive energy expenditure. Due to this labor-intensive nature of construction work, many construction workers face excessive demands beyond their physical capabilities. Thus, they are prone to be exposed to significantly high level of mental fatigue as well as other safety risks. This study aims to focus on the physiological measures of energy expenditure of workers leading to fatigue. Factors that were considered in the study are activity metabolic rate, heart rate, age, and body mass index. To objectively measure the mental fatigue experienced by the construction workers during the whole 8-hour shift, the Deary Liewald reaction time software was used. Statistical analysis is also employed to determine the significant differences in the factors identified among the 5 construction trades such as labor, mason, carpentry, steal work and plumbing using ANOVA. Correlation analysis is also used to identify relationship of factors to the fatigue level of construction workers. Results of the study revealed that all factors considered in the study have significant relationship to the fatigue experienced by workers among the 5 construction trades. And in order to develop measures to minimize mental fatigue level of workers, a suitable work-rest schedule is designed through the application of Monte Carlo simulation model having 9,125 runs, which generated a year worth of data for the 25 construction workers.