Chronic musculoskeletal pain (CMP) is an urgent global public health concern. Pain neuroscience education (PNE) is an intervention used in the management of CMP aiming to reconceptualise an individual’s understanding of their pain as less threatening. This mixed-methods review undertook a segregated synthesis of quantitative and qualitative studies to investigate the clinical effectiveness, and patients’ experience of, PNE for people with CMP. Electronic databases were searched for studies published between 01/01/2002 and 14/06/2018. Twelve randomised controlled trials (n = 755) that reported pain, disability and psychosocial outcomes and four qualitative studies (n = 50) that explored patients experience of PNE were included. The meta-analysed pooled treatment effects for PNE vs control had low clinical relevance in the short-term for pain (-3.20/100; 95%CI -6.66 to 0.27) and disability (-4.10/100; 95%CI -7.89 to -0.32) and the medium-term for pain (-4.22/100; 95%CI -16.44 to 8.01) and disability (-8.23/100; 95%CI -15.61 to -0.84). The treatment effect of PNE for kinesiophobia was clinically relevant in the short-term (-13.55/100; 95%CI -25.89 to -1.21) and for pain catastrophising in the medium-term (-5.26; 95%CI -10.59 to 0.08). Meta-synthesis of 23 qualitative findings resulted in the identification of two synthesized findings that identified several key components important for enhancing the patient experience of PNE such as allowing the patient to tell their own story. These components can enhance pain reconceptualisation, which appears to be an important process to facilitate patients’ ability to cope with their condition. The protocol was published on PROSPERO (CRD42017068436).