We compared the efficacy and early morphological changes in the cornea following conventional (C-CXL), transepithelial by iontophoresis (I-CXL), and accelerated (A-CXL) collagen cross-linking in keratoconus. A total of 45 eyes of 45 patients with progressive keratoconus who underwent corneal collagen crosslinking (CXL) was divided into three groups: C-CXL (n = 15), A-CXL (n = 15), and I-CXL (n = 15). Patients were examined before surgery and at 1-, 3-, and 6-month intervals following surgery. Density of corneal sub-basal nerves, anterior and posterior keratocytes, corneal endothelium, demarcation line depth, and maximal simulated keratometry values (Kmax) were all assessed. Compared to preoperative values, the mean corneal sub-basal nerve and anterior stromal keratocyte densities were significantly lower at 6 months in the C-CXL and A-CXL groups (P < 0.001), whereas they returned to preoperative values in the I-CXL group (P = 0.083 and P = 0.909, respectively). The corneal demarcation line was visible 1 month after surgery in 93% of cases (mean depth, 302.8 ± 74.6 μm) in the C-CXL group, 87.5% (mean depth, 184. 2 ± 38.9 μm) in the A-CXL group, and 47.7% (mean depth, 212 ± 36.5 μm) in the I-CXL group (P = 0.006). There were no significant differences between confocal microscopy and optical coherence tomography measurements of the corneal demarcation line depth (P > 0.05). The Kmax, corneal central thickness, and BSCVA remained stable during the whole study period. Iontophoresis was associated with weaker damage of corneal sub-basal nerves and anterior keratocytes compared to conventional procedures, but the demarcation line was present in less than 50% of cases and was more superficial than with the traditional procedure.