Abstract Background This study quantifies the longitudinal economic burden for a wide spectrum of incident complications, metabolic syndrome (MS)-related risk factors, and comorbidities in patients with MS. Methods This retrospective study utilized linked data from the 2013 National Health Interview Survey and the 2012–2021 National Health Insurance Research Database to identify MS individuals and their characteristics. The incidence rate of each complication was calculated as the number of complication events in the study period divided by the total person-years during follow-up. The healthcare costs of complications were analyzed using a generalized estimating equation model to determine the cost impact of complications after adjustment for patients’ characteristics. Sensitivity analyses on variables with high missing rates (i.e., cause of death, body mass index) were performed. Results Among 837 identified MS individuals over 8.28 (± 1.35) years of follow-up, the most frequent complications were microvascular diseases (incidence rate for nephropathy/retinopathy/neuropathy: 6.49/2.64/2.08 events per 100 person-years), followed by cardiovascular diseases (2.47), peripheral vascular diseases (2.01), and cancers (1.53). Death was the costliest event (event-year cost per person: USD 16,429) and cancers were the most expensive complications (USD 9,127−11,083 for non-MS- and MS-related cancers). Developing non-MS/MS-related cancers, cardiovascular diseases, and obesity-related medical conditions increased annual costs by 273% (95% CI: 181−397%)/175% (105−269%), 159% (118−207%), and 140% (84−214%), respectively. Microvascular diseases had the lowest cost impact on annual costs (i.e., 27% [17−39%]/27% [11−46%]/24% [11−37%] increases for nephropathy/neuropathy/retinopathy, respectively). Having existing comorbidities increased annual costs by 20% (osteoarthritis) to 108% (depression). Having morbid obesity (i.e., body mass index ≥ 35 kg/m2) increased annual costs by 58% (30−91%). Conclusions The economic burden from costly incident complications (i.e., cardiovascular diseases, peripheral vascular diseases, cancers), MS-related risk factors (i.e., morbid obesity), and comorbidities (i.e., depression) highlight the urgent need for early intervention to prevent MS and its progression. The comprehensive cost estimates reported in this study can facilitate the parameterization of economic analyses to identify cost-effective interventions for these patients.