Granular sludge is a promising biotechnology to treat sewage contaminated with pharmaceuticals due to its increased toxicity resistance. In this context, this study evaluated the potential of Ca2+ as a granulation precursor and how pharmaceuticals compounds (Loratadine, Prednisone, Fluconazole, Fenofibrate, Betamethasone, 17α-Ethinyl estradiol, and Ketoprofen) affect granulation. Continuous and intermittent dosages of Ca2+ in the presence and absence of pharmaceuticals were evaluated. The results showed that intermittent addition of Ca2+ reduces the time for anaerobic sludge granulation, and pharmaceuticals presence did not impair granulation. 10% of the granules presented mean diameters greater than 2.11 mm within 93 days with intermittent Ca2+ dosage in the pharmaceuticals’ presence. In contrast, no granules higher than 2.0 mm were observed with no precursor addition. The pharmaceuticals toxicity may have created a stress condition for the microbial community, contributing to more EPS production and a greater potential for granulation. It was also verified that pharmaceuticals’ presence did not decrease organic matter, total alkalinity, and volatile fatty acids removals. The 16S rRNA gene analysis revealed taxa resistance to recalcitrant compounds when pharmaceuticals were added. Besides, the efficiency of a granular sludge bioreactor (EGSB) was evaluated for pharmaceuticals removal, and Betamethasone, Fenofibrate, and Prednisone were effectively removed.