Increasing resistance to antimicrobial agents has contributed to an elevated risk of complications of infectious keratitis. Corneal collagen cross-linking (CXL) has been widely adopted for the management of keratoconus and post-refractive surgery corneal ectasia. It has recently been introduced as an option for treating keratitis due to multidrug resistant organisms. The purpose of this review is to discuss the rationale, safety, and evidence for CXL in infectious keratitis and its possible effect on ocular surface inflammation. Published data show that CXL is effective and safe as an adjunct to antibiotic treatment in selected cases of bacterial keratitis. The benefit of CXL probably varies according to the etiology of the infection.