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Background: Although COVID-19 vaccination has been effective in reducing severe illness and mortality, its differential clinical behavior in vaccinated and unvaccinated individuals during the early stages of the pandemic-especially in settings with partial coverage and real-world conditions-remains insufficiently characterized. Objective: To assess differences in clinical presentation, comorbidity prevalence, hospitalization, and mortality between vaccinated and unvaccinated patients diagnosed with SARS-CoV-2 during the early phase of the pandemic. Methods: An analytical cross-sectional study was conducted using 4625 electronic medical records of patients diagnosed with COVID-19 in Guerrero, Mexico, between 1 January and 31 December 2021. Variables included vaccination status, age, sex, comorbidities, symptom severity, clinical outcomes, and mortality. Statistical analyses involved chi-square tests, logistic regression for hospitalization probability, and Cox proportional hazards models for mortality risk. Results: Of the patients analyzed, 31.45% had received at least one vaccine dose. Fever, headache, cough, and anosmia were more frequent among vaccinated individuals (p < 0.001). Prostration and chest pain were strongly associated with hospitalization in both groups. In unvaccinated patients, smoking (OR = 4.75), obesity (OR = 3.85), and hypertension (OR = 2.94) increased hospitalization risk. Among vaccinated patients, diabetes mellitus (OR = 3.62) and hypertension (OR = 2.88) were key predictors. Vaccination was significantly associated with lower odds of hospitalization (OR = 0.38; 95% CI: 0.26-0.55) and reduced mortality risk (HR = 0.24; 95% CI: 0.08-0.71). Conclusions: Vaccination status was a significant protective factor for both hospitalization and mortality; however, clinical symptoms and comorbidity-related risks varied, highlighting the need for individualized patient management strategies.