This current paper aims to review the literature on the root canal configuration (RCC) and root structure of permanent mandibular premolars. To find the published scientific literature on the RCC of mandibular premolars up to July 2022, a systematic search of four electronic databases was performed. The studies were selected, rendering to a predetermined point of reference: “mandibular 2nd premolar”, “root and canal system”, “morphology of root and canal”, “root and canal configuration”, and “morphology”, along with “anatomy” and “mandibular premolars”. Cross-referencing along with screening through the bibliographies of the chosen articles resulted in the identification of further studies. In the current study, we examined 30 different articles, and we chose them based on the quality of research investigations. From 3471 retrieved studies, a total of 15981 mandibular 2nd premolars were observed in 30 studies. The mean JBI score for studies assessing the structure of the root, as well as the root canal of the mandibular 2nd premolar, was 7.78 ± 0.81. We have found a pooled prevalence of 91.82% for Vertucci class I root canal morphology and 78.63% pooled prevalence of single-rooted mandibular second premolar. A total of 8677 mandibular 1st premolars were observed in 22 studies. The mean JBI score for studies assessing the structure and anatomy of the root, as well as root canal of mandibular 1st premolar, was 7. 95 ± 0.85. We have found a pooled prevalence of 74.34% for Vertucci class I root canal morphology and 85.20% pooled prevalence of single-rooted mandibular 1st premolar. Mandibular first and second premolars were mostly single-rooted teeth (89.5–100%). The most frequently seen RCC is a 1-1-2-/2 (type V–Vertucci’s), followed by 1-1-2-/1 (type IV– Vertucci’s; type III–Weine’s), and finally RCC 2-2-2-1 (type IV–Vertucci’s; type III–Weine’s). Presently, the imaging of CBCT is the most used research approach for studying Mn2Ps’ structural characteristics.