Prosthetic joint infection (PJI) remains a major complication of arthroplasty, and a considerable proportion of cases present as culture-negative infections, creating diagnostic uncertainty and therapeutic challenges. This systematic review and meta-analysis compared the clinical characteristics, management strategies, and outcomes of culture-negative and culture-positive PJI. A comprehensive literature search of studies published between January 2000 and December 2024 identified 18 comparative studies including 6,214 patients, of whom 1,182 (19.0%) had culture-negative and 5,032 (81.0%) had culture-positive infection. Culture-negative PJI was significantly associated with prior antimicrobial exposure (58% vs 24%; RR 2.41; 95% CI 1.88–3.09), and empirical broad-spectrum or glycopeptide-based regimens were more frequently used in these cases. Surgical strategies such as debridement-antibiotics-implant-retention and staged revision procedures were applied at comparable rates in both groups. Overall treatment outcomes were similar, with no significant differences in success after two-stage revision, failure following DAIR, or mortality rates. These findings suggest that culture-negative PJI represents primarily a diagnostic rather than prognostic challenge, with outcomes comparable to culture-positive infections when evidence-based surgical pathways are followed. Improvement in microbiological yield, optimization of sampling and processing techniques, and antimicrobial stewardship remain essential to enhance the management of this clinically important subset of PJI.