Background: To study the impact of MRI characteristics and of targeted biopsy (TB) core number on the final grade group (GG) prediction. Materials and Methods: The cohort was 478 consecutive patients who underwent radical prostatectomy (RP) after positive mpMRI (multiparametric magnetic resonance imaging) followed by fusion TB. Endpoints were the upgrading and concordance rates between TB and RP specimens. Results: Upgrading rate after TB was 40.6%. Patients with upgrading had lower PIRADS (Prostate Imaging-Reporting and Data System) scores (p < 0.001), smaller lesion size (p = 0.017), fewer TB cores (p < 0.001), and lower TB density (p = 0.015) compared with cases with grade concordance. There was a significant continuous improvement in upgrading rate when TB core number per lesion increased from 56.3% to 25.6% when <2 or ≥5 TB cores were taken, respectively (p = 0.002). The minimal TB number per lesion to reduce upgrading risk to approximately 30%was 4 in PIRADS 3, and 3 in PIRADS 4–5 cases. Conclusions: Grade group prediction by TB is significantly improved by higher PIRADS score, larger lesion size, and increased TB per lesion. At least four TB cores should be taken in PIRADS 3 score lesions, whereas three cores seem enough in PIRADS 4–5 cases to improve GG prediction and limit upgrading risk.