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Background: Carpal tunnel syndrome (CTS) is the most common peripheral neuropathy of the upper limb and a frequent cause of disability. Objective: To analyze the association between social determinants of health (SDH) and physical activity with pain intensity and mental health in patients with CTS. Design: A cross-sectional study was conducted in patients with CTS awaiting surgery in two public hospitals in Chile. Methods: The SDH collected included: employment status, educational level and monetary income. The level of physical activity was defined according to compliance with WHO recommendations. Outcome measures included: Pain intensity (Visual Analog Scale), Symptoms of anxiety and depression (Hospital Anxiety and Depression Scale), and catastrophic thinking (Pain Catastrophizing Scale). The adjusted regression coefficient (β) for the association between SDH and physical activity with each outcome was obtained using multivariable linear regression models controlling for age, sex, body mass index and symptom duration. Results: Eighty-six participants were included (mean age 50.9 ± 10 years, 94% women). A high level of physical activity was associated with a 12.41 mm decrease in pain intensity (β = −12.41, 95%CI: −23.87 to −0.95) and a 3.29 point decrease in depressive symptoms (β = −3.29, 95%CI: −5.52 to −1.06). In addition, being employed was associated with a 2.30 point decrease in anxiety symptoms (β = −2.30; 95%CI: −4.41 to −0.19) and a high educational level was associated with a 7.71 point decrease in catastrophizing (β = −7.71; 95%CI: −14.06 to −1.36). Conclusion: Multidisciplinary care teams should be aware of the association between SDH and physical activity with physical and mental health.