Background: There is a paucity of data to assess the impact of the COVID-19 pandemic on persons with disabilities (PwDs) in India. About 27.4 million cases were reported as of 27 May 2021. The continuing pandemic in the form of subsequent waves is expected to have negative repercussions for the disabled globally, particularly in India, where access to health, rehabilitation, and social care services is very limited. Therefore, this study aimed to assess the impact of the COVID-19 pandemic and lockdown restrictions on PwDs in India. Objective: To determine the level of disruption due to COVID-19 and the associated countrywide lockdown restrictions on PwD in India during the first wave. Methods: Using a cross-sectional, mixed-methods approach, data were collected from a representative sample of 403 persons with disabilities in 14 states in India during the COVID-19 first wave at two different points in time (Lockdown and post-lockdown phase). Factors associated with the negative impact were examined using the Chi-square test for associations. The paired comparisons between ‘lockdown’ with the ‘post-lockdown’ phase are presented using McNemar’s test and the marginal homogeneity test to compare the proportions. Additionally, a subsample of the participants in the survey was identified to participate in in-depth interviews and focus group discussions to gain in-depth insights on the study question and substantiate the quantitative findings. The framework approach was used to conduct a thematic analysis of the qualitative data. Results: About 60% of the PwDs found it difficult to access emergency medical services during the lockdown, and 4.6% post lockdown (p < 0.001). Likewise, 12% found it difficult to access rehabilitation services during the lockdown, and 5% post lockdown (p = 0.03). About 76% of respondents were apprehensive of the risk of infection during the lockdown, and this increased to 92% post lockdown (p < 0.001). Parents with children were significantly impacted due to lockdown in the areas of Medical (p = 0.007), Rehabilitation (p = 0.001), and Mental health services (p = 0.001). The results from the qualitative study supported these quantitative findings. PWDs felt that the lockdown restrictions had negatively impacted their productivity, social participation, and overall engagement in everyday activities. Access to medicines and rehabilitation services was felt to be extremely difficult and detrimental to the therapeutic benefits that were gained by them during the pre-pandemic time. None of the pandemic mitigation plans and services was specific or inclusive of PWDs. Conclusions: COVID-19 and the associated lockdown restrictions have negatively impacted persons with disabilities during the first wave in India. It is critical to mainstream disability within the agenda for health and development with pragmatic, context-specific strategies and programs in the country.