The goal of Seguro Popular (SP) in Mexico was to improve the financial protection of the uninsured population against excessive health expenditures. This paper estimates the impact of SP on catastrophic health expenditures (CHE), as well as out-of-pocket (OOP) health expenditures, from two different sources. First, we use the SP Impact Evaluation Survey (2005–2006), and compare the instrumental variables (IV) results with the experimental benchmark. Then, we use the same IV methods with the National Health and Nutrition Survey (ENSANUT 2006). We estimate naïve models, assuming exogeneity, and contrast them with IV models that take advantage of the specific SP implementation mechanisms for identification. The IV models estimated included two-stage least squares (2SLS), bivariate probit, and two-stage residual inclusion (2SRI) models. Instrumental variables estimates resulted in comparable estimates against the “gold standard.” Instrumental variables estimates indicate a reduction of 54% in catastrophic expenditures at the national level. SP beneficiaries also had lower expenditures on outpatient and medicine expenditures. The selection-corrected protective effect is found not only in the limited experimental dataset, but also at the national level.