To determine whether dropless, injection-based cataract surgery prophylaxis with intracameral antibiotic and subconjunctival steroid may reduce healthcare system costs and patient out-of-pocket costs compared to topical medication regimens. United States national medical expenditures database. Retrospective cost analysis. Costs were analyzed for topical ophthalmics from the 2020 Medical Expenditure Panel Survey (MEPS) and for dropless medications from pharmaceutical invoices/catalogs. Main outcomes included system costs, from insurance and patient payments, and out-of-pocket costs for cataract surgery topical and dropless, injection-based prophylactic medication regimens, per eye and nationally. System costs for individual topical medications and same-class dropless, injection-based medications were compared using two-sided, one-sample t-tests. There were 583 prophylactic topical ophthalmic purchases in MEPS. Mean system costs per eye were $76.20 ± SD 39.07 for the lowest cost topical steroid (prednisolone) compared to $4.01 for the lowest cost subconjunctival steroid (triamcinolone acetonide) (p < 0.001). Per eye, the lowest cost dropless, injection-based regimen, at $15.91, results in an $87.99 (84.7%) reduction in overall healthcare costs and a $43.64 (100%) reduction in patient out-of-pocket costs relative to the lowest cost topical regimen ($103.90 ± 43.14 mean system cost and $43.64 ± 37.32 mean out-of-pocket cost per eye). Use of intracameral moxifloxacin and subconjunctival triamcinolone acetonide can reduce annual national healthcare system and out-of-pocket costs up to $450,000,000 and $225,000,000, respectively. An evidence-based cataract surgery prophylactic medication regimen of intracameral moxifloxacin and subconjunctival triamcinolone acetonide can reduce healthcare system and patient out-of-pocket costs in comparison to various topical regimens.