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Objective To compare the effectiveness and cost‐effectiveness of adrenocorticotropic hormone (ACTH) and oral steroids as first‐line treatment for infantile spasm resolution, we performed a systematic review, meta‐analysis, and cost‐effectiveness study. Methods A decision analysis model was populated with effectiveness data from a systematic review and meta‐analysis of existing literature and cost data from publicly available prices. Effectiveness was defined as the probability of clinical spasm resolution 14 days after treatment initiation. Results We included 21 studies with a total of 968 patients. The effectiveness of ACTH was not statistically significantly different from that of oral steroids (.70, 95% confidence interval [CI] = .60–.79 vs. .63, 95% CI = .56–.70; p = .28). Considering only the three available randomized trials with a total of 185 patients, the odds ratio of spasm resolution at 14 days with ACTH compared to high‐dose prednisolone (4–8 mg/kg/day) was .92 (95% CI = .34–2.52, p = .87). Adjusting for potential publication bias, estimates became even more favorable to high‐dose prednisolone. Using US prices, the more cost‐effective treatment was high‐dose prednisolone, with an incremental cost‐effectiveness ratio (ICER) of $333 per case of spasms resolved, followed by ACTH, with an ICER of $1 432 200 per case of spasms resolved. These results were robust to multiple sensitivity analyses and different assumptions. Prednisolone at 4–8 mg/kg/day was more cost‐effective than ACTH under a wide range of assumptions. Significance For infantile spasm resolution 2 weeks after treatment initiation, current evidence does not support the preeminence of ACTH in terms of effectiveness and, especially, cost‐effectiveness.