Background Firearm violence remains a persistent public health threat. Comparing the impact of targeted high-risk versus population-based approaches to prevention may point to efficient and efficacious interventions. We used agent-based modeling to conduct a hypothetical experiment contrasting the impact of high-risk (disqualification) and population-based (price increase) approaches on firearm homicide in New York City (NYC). Methods We simulated 800,000 agents reflecting a 15% sample of the adult population of NYC. Three groups were considered and disqualified from all firearm ownership for five years, grouped based on prevalence: low prevalence (psychiatric hospitalization, alcohol-related misdemeanor and felony convictions, 0.23%); moderate prevalence (drug misdemeanor convictions, domestic violence restraining orders, 1.03%); and high prevalence (all other felony/misdemeanor convictions, 2.30%). Population-level firearm ownership was impacted by increasing the price of firearms, assuming 1% price elasticity. Results In this hypothetical scenario, to reduce firearm homicide by 5% in NYC, 25% of the moderate prevalence group, or 12% of the high prevalence group needed to be effectively disqualified; even when all of the low prevalence group was disqualified, homicide did not decrease by 5%. An 18% increase in price similarly reduced firearm homicide by 5.37% (95% CI 4.43–6.31%). Firearm homicide declined monotonically as the proportion of disqualified individuals increased and/or price increased. A combined intervention that both increased price and effectively disqualified “high-risk” groups achieved approximately double the reduction in homicide as any one intervention alone. Increasing illegal firearm ownership by 20%, a hypothetical response to price increases, did not meaningfully change results. Conclusion A key takeaway of our study is that adopting high-risk versus population-based approaches should not be an “either-or” question. When individual risk is variable and diffuse in the population, “high-risk approaches” to firearm violence need to focus on relatively prevalent groups and be highly efficacious in disarming people at elevated risk to achieve meaningful reductions in firearm homicide, though countering issues of social justice and stigma should be carefully considered. Similar reductions can be achieved with population-based approaches, such as price increases, albeit with fewer such countering issues.