Abstract Background Pakistan has already encountered intense opposition to polio vaccination due to myths and misinformation, now the unfavorable opinions of COVID-19 vaccinations among the population would have catastrophic consequences for attempts to end the pandemic. Methods A web-based cross-sectional study was conducted in the general population of Sindh, Pakistan in January 2021. 31 items based on vaccines availability, safety, and myths, the questionnaire was designed and randomly distributed through a google form link. Results were analyzed using descriptive and Chi-square tests. Results A total of 774 responses were recorded from 23 districts of Sindh, Pakistan. The majority of participants (n=00, 00.0%) were not aware of the presence of the COVID-19 vaccine in Pakistan. Results found the significant relationship of conspiracies and myths with an education level of participants, to make Muslims infertile, illiterate showed (Yes n=45, No=27) while postgraduate (Yes n=11, No=88) (χ2 = 109.6, P> 0.000). Participants showed doubt about the safety of vaccines, (Yes n= 464, 59.9%, No= 310, 40.1%). Other responses related to side effects of the vaccine were also highly significant, participants showed that vaccine side effects (Yes n= 462, 59.7%, No= 312, 40.3%), Pregnant or breastfeeding women should not get vaccinated (Yes n= 468, 59.8%, No= 311, 40.1%) and people with underlying conditions should not get vaccinated (True n= 389, 50.3%, False= 385, 49.7%). Conclusion The proportion of varying public doubts in vaccines’ safety and efficacy and the presence of myths, conspiracies will be a major barrier to vaccine uptake.