Background: Coronavirus disease is a pandemic that has disrupted many human lives, threatening people’s physical and mental health. Each pandemic wave struck in different ways, infectiveness-wise and mortality-wise. This investigation focuses on critically ill patients affected by the last two variants, Delta and Omicron, and aims to analyse if any difference exists between the two groups. Methods: intensive care unit (ICU) COVID-19 consecutive admissions between 1 October 2021 and 31 March 2022 were recorded daily, and data concerning the patients’ demographics, variants, main comorbidities, ICU parameters on admission, and the outcome were analysed by a univariate procedure and by a multivariate analysis. Results: 65 patients were enrolled, 31 (47.69%) belonging to the Omicron versus 34 (52.31%) to the Delta group. The mortality rate was 52.94% for the Omicron group versus 41.9% for the Delta group. A univariate analysis showed that the Omicron variant was associated with total comorbidities number, Charlson Comorbidity Index (CCI), pre-existing pulmonary disease, vaccination status, and acute kidney injury (AKI). In stepwise multivariate analysis, the total number of comorbidities was positively associated with the Omicron group, while pulmonary embolism was negatively correlated with the Omicron group. Conclusion: Omicron appears to have lost some of the hallmarks of the Delta variant, such as endothelialitis and more limited cellular tropism when it comes to the patients in the ICU. Further studies are encouraged to explore different therapeutic approaches to treat critical patients with COVID-19.