The Sangan processing plant consists of four consecutive low-intensity magnetic separation steps with the same magnetic field intensity of 1300 Gauss for upgradation of iron ore. Hence, the iron ore minerals with lower magnetic susceptibility or interlocked with gangue minerals have no opportunity for upgradation, and proceed to the tailing dam. Flotation is a powerful technique for upgradation of these materials, and it is the focus of this research work. A sample of 43.09% Fe and 12.1% FeO was taken from the tailings of second step of magnetic separation. The ore minerals of the sample were determined to be magnetite and hematite. A concentrate of 67% Fe and mass recovery of 50% was produced through the Davis tube test. A reverse flotation route was selected for upgradation of the sample. Fatty acid-based anionic collectors with trade names Alke and Dirol were used in the flotation experiments. The design of experiments was done by resolution IV fractional factorial design with nine factors at two levels per factor. A resolution IV design allows discrimination of all main effects and two-factor interactions. A concentrate of 53.92% Fe at a mass recovery of 60% was obtained at optimum flotation conditions of solid content 20%, pH 12, collector concentration of 1 kg/t, starch as depressant at a concentration of 5 kg/t, Alke/Dirol collector mass ratio of 30/70, conditioning time of 10 min., and concentration of Ca2+ as activator 1 kg/t. In this research work, the concept of natural depression of iron minerals in the reverse flotation was introduced and evaluated.