(1) Background: Until December 2021, French Guiana (FG), located in South America, faced four consecutive COVID-19 epidemic waves. This study sought to analyze the mortality trend of severe COVID-19 patients admitted to the referral ICU of FG. (2) Methods: We conducted a prospective, observational, and non-interventional study in ICU at Cayenne Hospital. We included 383 patients older than 18 admitted with SARS-CoV-2-related pneumonia hospitalized from May 2020 to December 2021. The study covers three periods. Period 1 (Waves 1 and 2, original variant), period 2 (Wave 3, Gamma variant), and period 3 (Wave 4, Delta variant). (3) Results: The median age was 63 years (52–70). Frailty was diagnosed in 36 patients over 70 (32.4%). Only 4.8% of patients were vaccinated. The median ICU LOS was 10 days (6–19). Hospital mortality was 37.3%. It was 30.9% in period 1, 36.6% in period 2 (p = 0.329 vs. period 1), and 47.1% in period 3 (0.015 vs. period 1). In multivariate analysis, independent factors associated with hospital mortality included age greater than 40 years (]40–60 years] OR = 5.2, 95%CI: 1.4–19.5; (]60–70 years] OR = 8.5, 95%CI: 2.2–32; (]70+ years] OR = 17.9, 95%CI: 4.5–70.9), frailty (OR = 5.6, 95%CI: 2.2–17.2), immunosuppression (OR = 2.6, 95%CI: 1.05–6.7), and MV use (OR = 11, 95%CI: 6.1–19.9). This model had an overall sensitivity of 72%, a specificity of 80.4%, a positive predictive value of 68.7%, and a negative predictive value of 82.8%. (4) Conclusions: The mortality of severe COVID-19 patients in French Amazonia was higher during the Delta variant wave. This over-death could be explained by the virulence of the responsible SARS-CoV-2 variant and the under-vaccination coverage of the studied population.