Rest breaks are very important to prevent the accumulation of mental fatigue in sustained mental work environments. In this research, an integrated design and evaluation system for fatigue and relaxation is proposed, which consists of subjective scale, performance assessment and neurological signals. A work-rest schedule containing mental calculation and rest break is designed to reflect effect of prolonged cognitive work and rest time in mental work environments. Inter-individual difference has been taken into account to extract common features. The results indicate that rest breaks in sustained mental work are effective to counteract mental fatigue and improve work efficiency. Rest breaks are widely recommended in practical mental work circumstance. Integrated analysis from multi-estimators is helpful to improve the validity and explore the underlying mechanisms central to mental fatigue. Electroencephalogram (EEG) signals at occipital region show high correlation with performance. Thus EEG signals can contribute to the efficient design of work-rest schedule.