COVID-19 is no longer a public health emergency of international concern, but long COVID’s effects are yet to be fully understood. Hence, globally, SARS-CoV-2 is still a profound threat to public health and of perilous nature as a zoonotic disease. Timely vaccination provided to individuals worldwide during the pandemic phase was under a certain degree of control; however, few studies have reported the effectiveness of vaccines administered in Mexico, and its surveillance is paramount. Furthermore, an unknown proportion of Mexican individuals have not yet received any vaccine, and the circulation of the Omicron, Pirola, and FLiRT variants is ongoing. A cross-sectional serology survey study design was employed, involving 150 individuals from Southern Mexico (Oaxaca) whose humoral immune responses after vaccination were tested by an ELISA; the receptor-binding domain of the SARS-CoV-2 spike protein served as a recombinant antigen in the ELISA. One hundred thirty-nine out of 150 individuals (92.6%; 95%-CI = 87–95%) examined were positive for the ELISA, but in 11 individuals, the vaccines did not induce any immune response. Interestingly, the immune responses (antibody prevalence and levels) of females (58%) were higher (T= −2.21; p-value = 0.02) than those of males (41%). However, in this sample population of Southern Mexico, age, vaccine type, comorbidity, and body mass index did not have any effect (p > 0.05) after COVID-19 vaccination. Taking all results together, here, we present factors that affected immune responses of individuals during the first vaccination campaign in Oaxaca, Mexico; however, vaccine surveillance during the post-pandemic phase needs further investigation.