BACKGROUND: Monitoring long-term trends in cancer mortality is essential to guide prevention and control strategies. In Colombia, where national cancer incidence data are limited, mortality statistics provide a key source of epidemiological insight. We aimed to analyse long-term trends in sex differences in cancer mortality in Colombia between 1980 and 2023, examining variations by cancer type, age group, health insurance scheme, and urban-rural residence. METHODS: We analysed national mortality records (from the DANE) for 1980-2023. Fourteen cancer causes of death were defined using the International Classification of Diseases (ICD-9 and ICD-10). Age-standardised mortality rates per 100,000 population were calculated for individuals aged 20 years or older using Segi's world standard population. Mortality rate ratios (MRRs) were estimated as the ratio of male to female mortality overall and by age group. Years of life lost (YLLs) were calculated assuming a common life expectancy for both sexes. FINDINGS: Of 274,125 cancer deaths, 54.67% occurred in female individuals and 45.33% in male individuals. Until 1995, female individuals experienced higher mortality, with MR in the 1980s of 87.34 vs. 78.33 (male individuals) and a MRR of 0.90 (95% CI 0.89-0.90). Since 1996, this trend reversed, with MR in the 2020s of 69.23 for female individuals vs. 76.94 for male individuals (MRR: 1.11; 95% CI 1.10-1.12). Over the entire period, female individuals accumulated more YLLs than male individuals, 9.47 million vs. 7.51 million. The most notable sex gaps are observed in bladder (MRR 2.26), oesophageal (MRR 2.18), trachea, bronchus, and lung (MRR 1.72), and stomach cancer (MRR 1.66), with male individuals showing both higher mortality and greater YLL, particularly for stomach cancer. Despite these differences, overall cancer mortality has declined, especially among female individuals aged 50-79. INTERPRETATION: Long-term mortality trends reveal shifting sex-specific burdens and persistent disparities across cancer types in Colombia. These findings underscore the need for sex-informed prevention and control strategies. FUNDING: None.