Objective Although there has been increasing interest in the role of systemic cytokines in chronic spinal pain (CSP), the evidence on their potential contribution is still unclear. Therefore, the current study systematically reviewed the evidence on systemic cytokine level differences between people with CSP compared to healthy controls (HCs) and the potential associations with pain severity. Methods An electronic search was conducted on PubMed, Web of Science and Embase. All included studies were classified as observational studies, exploring the comparison between a CSP group and a HC group, and the association between systemic cytokine levels and pain severity. Results Nine articles were included with a total sample of 400 CSP patients suffering from chronic whiplash associated disorder (CWAD) or chronic low back pain (CLBP). In CLBP, moderate evidence was found for elevated tumor necrosis factor (TNF) α, interleukin (IL) 6, IL-1 receptor antagonist (IL-1RA), and soluble TNF receptor (sTNF-R) type 2, for normal interferon (IFN) γ and IL-2 levels, and for reduced IL-10 levels. No association was found between pain severity and these cytokines in CLBP. In CWAD, moderate evidence was found for elevated CRP and evidence for changes in TNF-α was inconclusive. Evidence for the association between pain severity and CRP was limited, and there is probably no association between pain severity and TNF-α with limited evidence in CWAD. Conclusions Moderate evidence indicates the presence of systemic inflammation in CSP. Evidence regarding the association between pain severity and systemic cytokines is inconclusive and limited.