Introduction: Chronic pain often persists despite peripheral interventions, with approximately 20–30% of patients showing poor responses, likely due to central sensitization (CS), a heightened central nervous system response that amplifies pain. This study aimed to systematically review and meta-analyze the relationship between CS and treatment outcomes following peripheral interventions. Method: A systematic review and meta-analysis were conducted, synthesizing evidence from 24 studies that examined the association between central sensitization and outcomes after peripheral treatments in chronic pain patients. The analyses assessed how CS influenced post-treatment pain intensity and clinical symptoms like functionality. Results: The systematic review revealed that patients with greater CS experienced poorer outcomes after peripheral interventions. The meta-analysis confirmed that higher levels of CS were significantly associated with increased pain severity and worse functionality following treatment. Heterogeneity among studies was partly explained by pain type, particularly chronic low back pain, which moderated both pain and health outcomes. Moreover, assessment methods, notably the use of the Central Sensitization Inventory (CSI) and Visual Analog Scale (VAS), moderated the relationship between CS and pain severity. No evidence of publication bias was detected, and findings remained robust in sensitivity analyses. Discussion: These results demonstrate a strong association between CS and poor response to peripheral treatments in chronic pain patients. The moderating role of chronic low back pain suggests that individuals with CS in this subgroup are especially vulnerable to suboptimal outcomes. Consequently, these findings highlight the importance of avoiding unnecessary invasive procedures and emphasize the need for tailored interventions targeting the central nervous system in patients exhibiting signs of CS, even when initially considered suitable for peripheral interventions.