This work investigated the self-cleaning performance of three drain modes in circular bottom drain water tanks with tangential inlet. Removal experiments in center, eccentric and center-eccentric combined (dual) drain modes were carried out in a miniature tank with a diameter of 0.44 m and a depth of 0.215 m for a hydraulic retention time of 30 min using two artificial bio-wastes mimicking fish fecal and uneaten feed matters. The experiments were simulated by using the Eulerian model of FLUENT. The correlations between the numerical solutions and the experimental data confirm the adequate reproduction of the bio-waste removal behavior. It was confirmed that the self-cleaning performance of the center drain is four times greater than that of the eccentric drain under the same water supply condition. Since the water drainage speeds of the dual-drain were less than those of the other two drains under the same water supply condition, the order of precedence for self-cleaning performance was the center drain, dual-drain, and eccentric drain. According to numerical experiments in the full-size tank with a diameter of 9.15 m and a depth of 1.83 m for hydraulic retention times of 30 and 55 min, the above order was kept constant, but the self-cleaning performance of the center drain was reduced by 1.04 times of that in the eccentric drain. The numerical experiments of all possible dual, triple and quadruple bottom drain modes in the full-size tank with one center drain and three eccentric drains showed that an increase of the eccentric drains causes a decrease of the drainage speed and thus does not lead to a noticeable improvement in self-cleaning performance. Numerical experiments in a medium-size tank showed that the above order was also kept constant. The reason why the self-cleaning performance of the center-eccentric combined drain is lower than that of the center drain is that its reduced drainage speed does not have kinetic energy enough to push the bio-wastes up to the height of the outlet. The center drain has the best self-cleaning performance in the circular tanks with tangential inlet and if the drainage speed is not sufficiently increased, the multiple drain system might have negative effect on self-cleaning performance.