Obesity is associated with an increased risk of contracting infections. This study aimed to estimate the risk of COVID-19 infection associated with obesity and to assess its role in the specific antibody response against SARS-CoV-2 in 2021. This study included 980 participants from the State of Mexico who participated in a serological survey where they were tested for SARS-CoV-2 IgG anti-S1/S2 and anti-RBD antibodies and asked for height, weight, and previous infection data via a questionnaire. Of the cohort of 980 participants, 451 (46.02%) were seropositive at the time of recruitment (45.2% symptomatic and 54.8% asymptomatic). The risk of SARS-CoV-2 infection with obesity was 2.18 (95% CI: 1.51–3.16), 2.58 (95% CI: 1.63–4.09), and 1.88 (95% CI: 1.18–2.98) for seropositive, asymptomatic, and symptomatic individuals, respectively, compared to those with normal weight. Anti-S1/S2 and anti-RBD IgG antibodies tended to be higher in overweight and obese participants in the seropositive group and stratified by different obesity classes. Additionally, there was a positive correlation between anti-S1/S2 and anti-RBD IgG antibodies and BMI in both men and women in the seropositive group. Obesity is an independent risk factor for SARS-CoV-2 infection when adjusted for confounding variables; however, the relationship between BMI and anti-S1/S2 and anti-RBD IgG antibody levels differed markedly in the presence or absence of symptoms.