Background Early and accurate detection of periprosthetic joint infection (PJI) after hip and/or knee arthroplasty remains challenging. This systematic review and meta-analysis of diagnostic test accuracy studies aimed to evaluate the diagnostic accuracy of serum and synovial fluid interleukin (IL)-6 in detecting PJI. Methods We searched 3 databases for studies through December 31, 2021, using medical sub-headings terms and keywords. Studies reported sensitivity and specificity of serum and synovial fluid IL-6 in detecting PJI were considered. We calculated the pooled sensitivity, specificity, positive and negative likelihood ratio, diagnostic odds ratio (DOR), and the area under the summary receiver operating characteristic curve (AUC) to evaluate the diagnostic accuracy of serum and synovial fluid IL-6. Results Thirty studies were included. The pooled sensitivity, specificity, positive and negative likelihood ratio, DOR, and AUC of serum IL-6 in detecting PJI were 0.76 (0.69–0.81), 0.88 (0.82–0.92), 6.2 (4.3–9.0), 0.28 (0.22–0.35), 22 (14–36), and 0.88 (0.85–0.91), respectively. However, synovial fluid IL-6 achieved a pooled sensitivity of 0.87 (0.75–0.93), specificity of 0.90 (0.85–0.93), positive and negative likelihood ratio of 8.5 (5.3–13.6) and 0.15 (0.08–0.29), DOR of 57 (21–156), and AUC of 0.94 (0.92–0.96), which were higher than serum IL-6. Conclusions Synovial fluid IL-6 test may be a promising test for PJI after hip and/or knee arthroplasty. However, considering the limited volume of synovial fluid and invasive acquisition of synovial fluid IL-6, serum IL-6 test may be also considered.