Background and purposeCollagen cross-linking (CXL) has evolved as an essential therapeutic approach for corneal infections, allowing for rapidly eliminating the infecting microorganism while reducing inflammation. This study aims to evaluate the efficacy of CXL as a monotherapy for managing infectious keratitis caused byFusarium solaniandPseudomonas aeruginosa.Materials and methodsForty-eight white New Zealand rabbits weighing approximately 1.5–2 KG were included. The cornea of one eye of each rabbit was inoculated with eitherFusarium solaniorPseudomonas aeruginosa. Group A served as a control and was subdivided into two subgroups, A1 and A2; each subgroup consisted of 8 eyes and was injected with eitherFusarium solaniorPseudomonas aeruginosa,respectively. Group B (16 eyes) was inoculated withFusarium solani, while group C (16 eyes) were inoculated withPseudomonas aeruginosa. All animals in Group B and C received CXL treatment one week after inoculation of the organisms and after corneal abscess formation was confirmed. At the same time, animals in Group A were left untreated.ResultsThere was a statistically significant reduction in the number of colony-forming units (CFU) in Group B following CXL. No growth existed in any samples at the end of the 4th week. There was a statistically significant difference in the number of CFU between group B and the control group (p< 0.001). In group C, there was a statistically significant reduction in the CFU at the end of the first week after CXL. However, there was regrowth in all samples afterward. All 16 models in Group C showed uncountable and extensive growth during the subsequent follow-ups. There was no statistically significant difference between the number of CFU in Group C and the control group. Histopathology showed lesser corneal melting in CXL-treatedPseudomonas aeruginosa.ConclusionsCollagen cross-linking is promising monotherapy and alternative treatment in managing infective keratitis caused byFusarium solanibut is less effective inPseudomonas aeruginosaas monotherapy.