Background: The diagnostic performance of numerous clinical specimens to diagnose COVID-19 through RT-PCR techniques is very important, and the test result outcome is still unclear. This review aimed to analyze the diagnostic performance of clinical samples for COVID-19 detection by RT-PCR through a systematic literature review process. Methodology: A compressive literature search was performed in PubMed/Medline, Scopus, Embase, and Cochrane Library from inception to November 2022. A snowball search on Google, Google Scholar, Research Gate, and MedRxiv, as well as bibliographic research, was performed to identify any other relevant articles. Observational studies that assessed the clinical usefulness of the RT-PCR technique in different human samples for the detection or screening of COVID-19 among patients or patient samples were considered for this review. The primary outcomes considered were sensitivity and specificity, while parameters such as positive predictive value (PPV), negative predictive value (NPV), and kappa coefficient were considered secondary outcomes. Results: A total of 85 studies out of 10,213 non-duplicate records were included for the systematic review, of which 69 articles were considered for the meta-analysis. The meta-analysis indicated better pooled sensitivity with the nasopharyngeal swab (NPS) than saliva (91.06% vs. 76.70%) and was comparable with the combined NPS/oropharyngeal swab (OPS; 92%). Nevertheless, specificity was observed to be better with saliva (98.27%) than the combined NPS/OPS (98.08%) and NPS (95.57%). The other parameters were comparable among different samples. The respiratory samples and throat samples showed a promising result relative to other specimens. The sensitivity and specificity of samples such as nasopharyngeal swabs, saliva, combined nasopharyngeal/oropharyngeal, respiratory, sputum, broncho aspirate, throat swab, gargle, serum, and the mixed sample were found to be 91.06%, 76.70%, 92.00%, 99.44%, 86%, 96%, 94.4%, 95.3%, 73.63%, and above 98; and 95.57%, 98.27%, 98.08%, 100%, 37%, 100%, 100%, 97.6%, and above 97, respectively. Conclusions: NPS was observed to have relatively better sensitivity, but not specificity when compared with other clinical specimens. Head-to-head comparisons between the different samples and the time of sample collection are warranted to strengthen this evidence.