Despite growing numbers of scientific publications on the optimal antibiotic treatment for diabetic foot infections, the data on the adult population with non-diabetic (postsurgical) foot infections is limited. Therefore, one of the largest single-center databases at the Balgrist University Hospital in Zurich, Switzerland, was established between January 2014 and August 2022. Using a case–control study design, we retrospectively investigated failures of combined surgical and antibiotic therapy for surgical site foot infections (SSIs). Overall, 17.4% of the episodes experienced therapeutic failures, particularly in patients with infected ankle prostheses. However, age, biological sex, pathogens, the duration of post-debridement antibiotic treatment, the number of surgical debridements, or the use of negative-pressure wound care altered the failure risk. In the multivariate logistic regression analyses, the duration of postsurgical antibiotic use was completely indifferent (as a continuous variable with an odds ratio of 1.0 and a 95% confidence interval ranging from 0.96 to 1.03) when stratified into inter-tertiary groups. Our findings suggest that shorter courses of systemic antibiotics may be appropriate in non-diabetic adults, supporting better antibiotic stewardship. Ongoing randomized controlled trials are under way to investigate which patients might safely receive shorter antibiotic treatments for surgical site infections following elective foot and ankle procedures.