Objectives: This systematic review analyzed the root canal morphology and configuration (RCC) of maxillary first premolars (Mx1Ps) and sex-specific differences based on existing literature. Methods: Registered in PROSPERO (CRD42023394460) and following PRISMA guidelines, systematic searches were conducted in five databases (Cochrane, Embase, LILACS, Scopus, MEDLINE via PubMed) using predefined MeSH terms. Additional studies were identified through cross-referencing. Studies on Mx1P RCCs were included, assessed using the AQUA tool. Data extraction focused on RCC prevalence, sex differences, root variations, and examination methods. Results: Of 865 studies, 86 were included, analyzing 31,325 teeth. The most common RCCs were 2-2-2/2 (IV, frequencies between 0.6–80.5%) and 1-1-1/1 (I, 1.1–72.0%). Mx1Ps primarily had two roots (7.1–96.2%) or one root (3.8–93.2%), with three-rooted variants being rare (0.4–6.5%). Males more frequently exhibited two- or three-rooted Mx1Ps with RCCs like 2-2-2/2 (IV; OR = 1.39 [1.22, 1.58]), and 1-1-3/3 (VIII; OR = 2.22 [1.59, 3.11]). Females showed higher frequencies of RCCs like 1-1-1/1 (I; OR = 0.71 [0.53, 0.96]), 2-2-1/1 (II; OR = 0.66 [0.57, 0.77]), 1-2-1/1 (III; OR = 0.70 [0.59, 0.83]), and 1-1-2/2 (V; OR = 0.81 [0.70, 0.95]). Conclusions: Mx1Ps predominantly have two roots and a 2-2-2/2 (IV) RCC. CBCT was the most used method, followed by staining and clearing. Clinicians should consider sex-specific and morphological variations.