Background: Sickle cell disease (SCD) is one of the most common monogenic disorders worldwide and remains associated with substantial mortality in low- and middle-income countries. In Colombia, population-level evidence on long-term mortality trends and socioeconomic inequalities in SCD is limited. Methods: We conducted an ecological time-series study using death certificate data from the Colombian National Administrative Department of Statistics (DANE). Age-standardized mortality rates (ASMRs) were calculated using the WHO world standard population. Temporal trends were assessed using joinpoint regression and mixed-effects Poisson models. Departments were classified into tertiles of socioeconomic development using the Multidimensional Poverty Index. Additional analyses examined differences by sex and urban–rural residence, and interrupted time-series and excess mortality analyses assessed the COVID-19 period (2020–2021). Results: A total of 675 SCD-related deaths were recorded between 2012 and 2023. The national ASMR increased from 0.055 per 100,000 in 2012 to 0.143 per 100,000 in 2023. In mixed-effects Poisson models, mortality increased (rate ratio [RR] per year = 1.03; 95% CI: 1.01–1.06; p = 0.002). Joinpoint analysis showed a rising trend among males (AAPC = + 8.20%; 95% CI: 0.98 to 15.24; p = 0.029). Mortality varied across departments, with the highest rates in Caribbean regions. Departments with low socioeconomic development had higher mortality than those with high development (RR = 3.00; 95% CI: 1.19–7.61; p = 0.020), and this association strengthened after adjustment for sex and area of residence (RR = 4.00; 95% CI: 1.60–9.97; p = 0.003). During 2020–2021, observed deaths were lower than expected based on pre-pandemic trends (standardized mortality ratio = 0.80; 95% CI: 0.68–0.95). Conclusions: SCD mortality in Colombia increased between 2012 and 2023, marked by territorial and socioeconomic inequalities. The apparent decline during the COVID-19 period likely reflects under-registration rather than a true reduction in mortality.