Background: Mandibular flexion (MF) is a complex biomechanical phenomenon, which involves a deformation of the mandible, due mainly to the contraction of the masticatory muscles, and it can have numerous clinical effects. The deformation of the lower jaw caused by mandibular flexion is generally very small, and it is often overlooked and considered irrelevant from a clinical point of view by many authors; however, it should be important to remember that median mandibular flexure (MMF) has a multifactorial aetiology. The main aim of the current systematic review is to highlight the different factors that can increase MF in order to help clinicians identify patients to whom they should pay more attention. As a secondary outcome, we wanted to analyse the preventive measures and suitable techniques to be adopted to minimise the negative effects of this phenomenon on oral fixed rehabilitations. Methods: The review, which was carried out in accordance with the “Preferred Reporting Items for Systematic reviews and Meta-Analyses” (PRISMA) flowchart, was recorded in the “International Prospective Register of Systematic Reviews” (PROSPERO). As research questions, “Patient/Population, Intervention, Comparison and Outcomes” (PICO) questions were employed. Using the ROBINS-I technique, the risk of bias in non-randomised clinical studies was evaluated. Results: The initial electronic search identified over 1300 potential articles, of which 54 studies were included in this systematic review. Information regarding the relationship between MF and individual factors, mandibular movements, impression taking, and fixed rehabilitations were obtained. Conclusions: The studies included in this systematic review showed that MF is greater during protrusive movements, in the posterior areas of the lower jaw, and in patients with brachial facial type, greater jaw length; small gonial angle; and less density, length, and bone surface of the symphysis. The biomechanical effects of mandibular flexion on fixed restorations are debated. Prospective clinical and radiological observational studies should be conducted to evaluate the potential short-, medium-, and long-term consequences of MF.