Background: Pakistan has subpar childhood immunization rates and immunization activities have faced several challenges over the past years. We evaluated the social-behavioral and cultural barriers and risk factors for refusal of polio, Routine Immunization (RI), or both in high-risk areas of poliovirus circulation. Methods: A matched case-control study was conducted from April to July 2017 in eight super high-risk Union Councils of five towns in Karachi, Pakistan. A total of 3 groups, each with 250 cases, including refusals for the Oral Polio Vaccine (OPV) in campaigns (national immunization days and supplementary immunization activities), RI, and both, were matched with 500 controls and identified using surveillance records. Sociodemographic characteristics, household information, and immunization history were assessed. Study outcomes included social-behavioral and cultural barriers and reasons for vaccine refusal. Data were analyzed in STATA using conditional logistic regression. Results: RI refusal was associated with illiteracy and fear of the vaccine’s adverse effects, while OPV refusals were linked to the mother’s decision authority and the assumption that the OPV caused infertility. Conversely, higher socioeconomic status (SES) and knowledge of and willingness to vaccinate with Inactivated Polio Vaccine (IPV) were inversely associated with RI; and lower SES, walking to the vaccination point, knowledge of IPV, and an understanding of contracting polio were inversely associated with OPV refusals, with the latter two also inversely associated with complete vaccine refusal. Conclusion: Education, knowledge and understanding of vaccines, and socioeconomic determinants influenced OPV and RI refusals among children. Effective interventions are needed to address knowledge gaps and misconceptions among parents.