Micro, small and medium enterprises (MSMEs) are resource constrained largely on account of their economic size, and they usually do not have required resource capacity to take advantage of entrepreneurial opportunities available on the policy ecosystem. There has been a large amount of research on financial interventions to boast MSMEs but scholars have overlooked the nexus between MSMEs-entrepreneurship infrastructural policy intervention and entrepreneurial orientation (EO) of MSMEs in Nigeria. Therefore, the paper aims to ascertain the relationship between infrastructure resource support of the National Enterprise Development and EO of MSMEs in Nigeria. The study adopted an analytic descriptive survey design. The population of the study is 3,455 MSMEs and a sample of 342 MSMEs was selected through a stratified random sampling method. The data collection instrument was a structured questionnaire, which was validated through a content validity approach. The internal consistency of the measurement instrument was ascertained using Cronbach alpha, with coefficients ranging from 0.72 and 0.79. The data were collected from managers of MSMEs and were analysed with Structural Equation Modelling (SEM) with a single step process approach. The study found that there was a positive significant relationship between entrepreneurship infrastructure policy and innovative orientation, proactive orientation, and risk-taking orientation of MSMEs (β = 0.278, t = 8.101, p < 0.05; β = 0.131, t = 2 549, p < 0.05; β = -0.008, t = 0. 004, p > 0.05). The study concluded that infrastructure resource support programme of the Federal Government stimulated innovative, proactive and risk-taking entrepreneurial behavior of MSMEs in Nigeria. The study recommended that infrastructural interventions should continue with a view to providing a robust policy environment for MSMEs to take advantage of entrepreneurial opportunities in Nigeria.