BackgroundManuscript preparation and the (re)submission of articles can create a significant workload in academic jobs. In this exploratory analysis, we estimate the time and costs needed to meet the diverse formatting requirements for manuscript submissions in biomedical publishing.MethodsWe reviewed 302 leading biomedical journals’ submission guidelines and extracted information on the components that tend to vary the most among submission guidelines (the length of the title, the running title, the abstract, and the manuscript; the structure of the abstract and the manuscript, number of items and references allowed, whether the journal has a template). We estimated annual research funding lost due to manuscript formatting by calculating hourly academic salaries, the time lost to reformatting articles, and quantifying the total number of resubmissions per year. We interviewed several researchers and senior journal editors and editors-in-chief to contextualize our findings and develop guidelines that could help both biomedical journals and researchers work more efficiently.ResultsAmong the analyzed journals, we found a huge diversity in submission requirements. By calculating average researcher salaries in the European Union and the USA, and the time spent on reformatting articles, we estimated that ~ 230 million USD were lost in 2021 alone due to reformatting articles. Should the current practice remain unchanged within this decade, we estimate ~ 2.5 billion USD could be lost between 2022 and 2030—solely due to reformatting articles after a first editorial desk rejection. In our interviews, we found alignment between researchers and editors; researchers would like the submission process to be as straightforward and simple as possible, and editors want to easily identify strong, suitable articles and not waste researchers’ time.ConclusionsBased on the findings from our quantitative analysis and contextualized by the qualitative interviews, we conclude that free-format submission guidelines would benefit both researchers and editors. However, a minimum set of requirements is necessary to avoid manuscript submissions that lack structure. We developed our guidelines to improve thestatus quo, and we urge the publishers and the editorial-advisory boards of biomedical journals to adopt them. This may also require support from publishers and major international organizations that govern the work of editors.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12916-023-02882-y.