Circulating tumor DNA (ctDNA) profiling offers non-invasive insights for personalized prostate cancer management. This systematic review provides the first comprehensive appraisal of ctDNA assay methods, genomic targets, and their clinical correlations and proposes practical recommendations to guide future standardization and validation. We searched PubMed, ScienceDirect, Scopus, and the Cochrane Library starting December 2024 following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines. From 229 records, 44 studies (10,631 patients) met the inclusion criteria. Plasma ctDNA analyzed by NGS predominantly profiled TP53 (72.7%), AR (70.4%), BRCA1/2 (61.3%), ATM (50%), RB1 (47.7%), and PTEN (41%). ctDNA positivity and specific key alterations correlated with poorer overall and progression-free survival. BRCA1/2-mutant patients benefited from Olaparib plus Abiraterone, while persistent alterations predicted early progression. Beyond synthesizing existing evidence, we identify key gaps, such as inconsistent reporting of variant allele fractions, limited diversity in study populations, and underexplored rare alterations. We recommend unified reporting standards (e.g., variant allele frequency thresholds and panel composition) and prioritized prospective trials to validate high-impact targets. These steps will accelerate the integration of ctDNA into routine precision oncology practice worldwide.