The coronavirus disease 2019 (COVID-19) pandemic has left no person unexposed to the wisdom about the need for human preparedness to tackle future pandemics irrespective of individual caste, race, religion, and education status. The extent of this change in knowledge and public perspective is difficult to measure in a populous nation like India subjected to individual freedom and cultural beliefs. Hence, we planned this study with the objective of evaluating the knowledge and perception of the Indian public towards COVID-19 disease, vaccination and research activities associated with the COVID-19 pandemic. This is an observational, single-center, cross-sectional study (n = 244) conducted after obtaining approval from the Ethics Committee for Academic Research Projects. All consenting study participants, Indian residents aged > 18 years, were administered a prevalidated and structured questionnaire and interviewed for their honest opinion. The outcome measures were to evaluate the knowledge and perception of the study participants in each of the domains of COVID-19 disease, COVID-19 vaccination, and COVID-19-related clinical research. Demographic characteristics were summarized using descriptive statistics. All analyses were done at a 5% significance level using GraphPad InStat version 3.1. Data on the proportion of participants' responses to the questions in each of the three domains of COVID-19 disease (D), COVID-19 vaccination (V), and COVID-19-related research (R) were assessed. Study participants who knew the causative agent for coronavirus disease were 93.03% (227/244), nomenclature (77.45%, 189/244), those who could define pandemic (89.34%, 218/244), preventive measures against covid (96.31%, 235/244), lungs as the most common organ affected (96.31%, 235/244) and all answered that the origin of novel coronavirus was China. The majority of them felt that COVID-19 pandemic waves would never end (39.34%, 96/244), there was no effective drug/vaccine therapy available, and the lack of oxygen/hospital beds (39%) resulted in maximum mortality, and 47.13% (115/244) were worried about future bioterrorism. The lockdown measures were justified by 161/244 (65.98%), and 93.85% supported lockdown measures to curb the spread of infection. The improvement in air quality/environment hygiene, realizing the importance of hygiene, vaccine and disease, and spending quality time with family were the best three things to happen during the pandemic, while the loss of wages, nonavailability of medicines/vaccines/oxygen/hospital beds with mental/physical health deterioration were the worst three things experienced by people. Regarding COVID-19 vaccination, the most common reason to get vaccinated was to prevent infection/critical outcomes of COVID-19 (78.27%, 191/244); 79% already suffered COVID-19 prior to vaccination, while 68.85% suffered a COVID-19 infection after taking the vaccine which was mostly asymptomatic/mild. Almost 56.96% (139/244) participants supported compulsory vaccination for all in the larger interest of society and to prevent fatal COVID-19 outcomes. There were safety concerns mainly with accelerated approval of vaccines (4.1%, 10/244) among the public, and 32.78% (80/244) attributed limited infrastructure/vaccination centers/healthcare staff as the major challenge of a mass vaccination program with 71.72% (175/244) supporting the vehicle/home vaccination drives to meet the vaccination demand in the pandemic. Approximately 38.11% (93/244) blamed the lack of sufficient vaccine manufacturing sites in India as a major vaccine shortage. Almost 82% public knew that vaccines are incapable of providing lifelong immunity or conferring protection against multiple variants, with 34.83% desiring to get polyvalent vaccines that would provide immunity against multiple COVID-19 variants. A total of 57.37% knew about clinical research, believed that the vaccine/drug development process was slow in India (29.91%), that there was a lack of funds invested in COVID-19-related clinical research (62.29%), 47.95% felt no attention was given to the alternative system of medicines, 77.86% supported accelerated drug/vaccine approval in the pandemic. Around 64.34% of the study, participants knew about the available and approved COVID-19 treatment options, such as antiviral drugs, monoclonal antibodies and vaccines. Of the total 244 study participants, 98.36% believed that clinical research is important for science to progress. When asked about their willingness to participate in COVID-19 clinical research, only 40.57% agreed, while 29% opted for non-COVID-19 related clinical research, and 29% refused to participate in any kind of clinical research. Almost 88.93% refused to take medicines without approval by drug regulatory bodies, and 54.51% agreed to participate in a controlled human challenge research study during the pandemic. The majority were of the opinion that lack of financial support (35.24%) was the main hindrance to the conduct of clinical research in India and the reason for lagging behind other countries in research and development (64.34%). The survey provides insight into the public awareness and perception of the pandemic that has taught all the lessons for capacity building in automation, construction of robust medical infrastructure, and the need for future preparedness. How to cite this article: Munshi R, Maurya M. A Cross-sectional Survey of Public Knowledge and Perspective on Coronavirus Disease, Vaccination, and Related Research in India during the COVID-19 Pandemic. J Assoc Physicians India 2023;71(9):19-27.