Background: Chest low-dose computed tomography (LDCT) is a promising technology for population-based screening because it is non-invasive, relatively inexpensive, associated with low radiation and highly sensitive to lung cancer. To improve the cost-effectiveness of lung cancer screening, simultaneous screening for other diseases could be considered. This systematic review was conducted to analyse studies that published evidence on the cost-effectiveness of chest LDCT screening programs for different diseases. Methods: Scopus and PubMed were searched for English publications (1 January 2011–22 July 2022) using search terms related to screening, computed tomography and cost-effectiveness. An additional search specifically searched for the cost-effectiveness of screening for lung cancer, chronic obstructive pulmonary disease or cardiovascular disease. Included publications should present a full health economic evaluation of population screening with chest LDCT. The extracted data included the disease screened for, model type, country context of screening, inclusion of comorbidities or incidental findings, incremental costs, incremental effects and the resulting cost-effectiveness ratio amongst others. Reporting quality was assessed using the 2022 Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results: The search yielded 1799 unique papers, of which 43 were included. Most papers focused on lung cancer screening (n = 40), and three were on coronary calcium scoring. Microsimulation was the most commonly applied modelling type (n = 16), followed by life table analysis (n = 10) and Markov cohort models (n = 10). Studies reflected the healthcare context of the US (n = 15), Canada (n = 4), the UK (n = 3) and 13 other countries. The reported incremental cost-effectiveness ratio ranged from US$10,000 to US$90,000/quality-adjusted life year (QALY) for lung cancer screening compared to no screening and was US$15,900/QALY–US$45,300/QALY for coronary calcium scoring compared to no screening. Discussion: Almost all health economic evaluations of LDCT screening focused on lung cancer. Literature regarding the health economic benefits of simultaneous LDCT screening for multiple diseases is absent. Most studies suggest LDCT screening is cost-effective for current and former smokers aged 55–74 with a minimum of 30 pack-years of smoking history. Consequently, more evidence on LDCT is needed to support further cost-effectiveness analyses. Preferably evidence on simultaneous screening for multiple diseases is needed, but alternatively, on single-disease screening. Registration of systematic review: Prospective Register of Ongoing Systematic Reviews registration CRD42021290228 can be accessed https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=290228.