Curcumin is a natural polyphenol with anti-inflammatory and anticancer potential, but its poor aqueous solubility and limited incorporation into polymeric carriers hinder clinical translation. Covalent or ion-paired conjugation with a polymeric matrix may enhance drug retention and loading, thereby improving delivery efficiency. This study investigated whether introducing acidic conditions to oil-in-water emulsification would promote curcumin–polyanhydride conjugation and improve encapsulation efficiency (EE) and drug loading (DL) in poly(sebacic anhydride) (PSA) microparticles (MPs). The results obtained by fluorimetry show that encapsulation outcomes strongly depended on the acid used. Trifluoroacetic acid (TFA) yielded negligible curcumin incorporation, with EE ranging from 1.7 ± 0.1% to 19.7 ± 0.6% and DL between 0.28 ± 0.01% and 3.3 ± 0.1%. In contrast, hydrochloric acid (HCl) and sulfuric acid (H₂SO₄) produced results comparable to non-acidified controls, with EE around 30–35% and DL around 5–6%. A markedly different outcome was observed with 2% aqueous trichloroacetic acid (TCA). Condition X21 exhibited the best performance with 53.6 ± 0.5% (EE) and 8.9 ± 0.1% (DL), while another TCA-based formulation (X20) also showed high encapsulation values (EE = 45.5 ± 1.1%, DL = 7.6 ± 0.2%). However, despite this significant improvement in curcumin incorporation, TCA-derived MPs compromised L929 fibroblasts viability, whereas HCl- and H₂SO₄- treated formulations were cytocompatible. These findings demonstrate that low-concentration aqueous TCA enhances curcumin incorporation into PSA MPs, likely via conjugate formation, but compromises cytocompatibility due to residual TCA. Further optimization of TCA concentration and purification steps will be necessary to balance drug loading with safety for biomedical applications.