This study investigates the effectiveness of coagulation-flocculation and sedimentation (CFS) for separating microalgae, focusing on the use of various Moringa oleifera extracts as natural coagulants. We examined photobioreactor effluent (PBR) both with and without microplastic PVC (MP-PVC) contamination, referred to as PBR R2 and PBR R1, respectively. Utilising response surface methodology, we identified optimal conditions for the removal of microalgae and MP-PVC. Validation tests demonstrated that the aqueous extract of delipidated Moringa oleifera powder (AEDMOP) achieved high removal efficiencies, with coagulant dosages of 630 mg L−1 for PBR R1 and 625 mg L−1 for PBR R2. Both conditions showed microalgae removal efficiencies exceeding 83% for turbidity, colour, OD540 nm, OD680 nm, and OD750 nm, and 63% for OD254 nm. Interestingly, the optimised conditions for PBR R2 required slightly less coagulant, likely due to the additional particulate matter from MP-PVC. While extracellular polymeric substances (EPS) exhibited a marginal effect on flocculation, further investigation into their role in CFS is necessary. Our findings highlight the potential of AEDMOP for efficient microalgae separation, even in the presence of microplastics.