This paper develops a Quadruple-Sextuple Helix framework of analysis to investigate the nexus disability and employment. It builds on the path breaking Triple Helix framework developed by Etzkowitz and Leydesdorff and the Quadruple-Quintuple Helix frameworks developed by Carayannis and Campbell. We argue that a Quadruple-Sextuple Helix framework of analysis provides a comprehensive approach to understand the opportunities and challenges permeating the nexus between disability and employment. We assembled a sample of 37 nations to test the notion that nations that are able to build cohesive and harmonious Quadruple-Sextuple Helix frameworks will be better capable of fostering the creation of jobs for their people with disabilities. These countries span different levels of economic and social development. The results indicate that the proposed quadruple and sextuple helix models can provide a better understanding of the disparities in unemployment for people with disabilities amongst the nations surveyed.