Numerous researchers have addressed the complexity of the direct flotation separation of apatite from low-grade phosphate ore. The majority of these studies were limited to the micro-flotation scale. In fact, there is no warranty that a reagent scheme that showed a direct flotation of apatite at a micro-flotation scale on pure minerals would automatically replicate the same expected results on the natural ore in the mechanical flotation cell and so was the case for the phosphate ore studied. The overall trend was concentrating apatite in the non-float product. This study aspired to thoroughly assess the flotation performance of this never-exploited low-grade sedimentary phosphate using design of experiments (DOE). Unveiling new insights on such a strategy twist, various parameters and operating conditions, namely, desliming, type of collector and depressant, reagents dosages, conditioning times, flotation time, and pH, were addressed by multiple-factor screening using asymmetrical fractional factorial design followed by statistical interpretations. The collectors tested were the sodium oleate and a fatty acid mixture (FAM). The depressants tested were sodium alginate (NaAL), corn starch, carboxymethylcellulose (CMC), and sodium silicate. The results of the multivariable analysis revealed that desliming, pH, collector dosage, and flotation time significantly influenced the flotation process. Desliming was beneficial for the yield, P2O5 recovery, and SiO2 removal; however, there was still a compromise between grade and recovery. A strongly alkaline pH value of 12 stood out from the whole range. P2O5, CO2, and SiO2 grades of the products and flotation recoveries were improved, except for P2O5 recovery, which was negatively affected. A collector dosage between 2000 and 3000 g/t increased the P2O5 grade and reduced CO2 grade and recovery, enhancing the apatite/carbonates separation. A flotation time of 15 min was significant for P2O5 grade and CO2 recovery, nevertheless, at the expense of yield and P2O5 recovery. The products having initial concentrates of 28.08% P2O5 with a recovery of 88.96% and 29.41% P2O5 with a recovery of 62.71% were obtained using 25 g/t of NaAL and 2000 g/t of the collector FAM and sodium oleate, respectively, at pH 12.