Cryptocaryon irritans protomont is important for encystation and division to continue the reinfection events. Microtubules play a determinant role in multiple cell processes such as: motility, intracellular transport, division, encystation and excystation. To evaluate the significance of microtubule cytoskeleton in Cryptocaryon irritans encystation and cyst proliferation, taxol (a tubulin polymerizing agent) and vinorelbine (a tubulin depolymerizing agent) were used. Using a structure-activity approach, their effects on the regulation of encystment, cyst proliferation, division, morphology, and encystment-related gene expression were assessed. Following collection, protomonts were exposed to serial concentrations of taxol (25, 50, 100, 250, and 500 μM) and vinorelbine (100, 250, 500, 750, and 1000 μM) for 1, 2, 3, and 12 h. Survival, encystation rate, excystation number of theronts, and theront body size decreased with varying degrees of time and concentration. Furthermore, the effects of anti-tubulins on the micro- and ultrastructure of protomonts were examined using the most feasible concentrations of 250 μM taxol and 500 μM vinorelbine. Microstructure observations for one cell cycle revealed delayed/incomplete encystation, change in cell symmetry, and delayed excystation process. Ultrastructure observations showed aggregation of microtubule bundles and disruption of microtubule assembly in the cytoplasm and around the cell wall of taxol- and vinorelbine-treated protomonts respectively. Inhibited microtubules altered ultrastructure resulting in fragile/fragmentary cyst wall formation. mRNA expression of α- and β-tubulin in the taxol-treated cells was significantly up-regulated when compared with the control (P˂0.05). In contrast, vinorelbine treatment markedly down-regulated mRNA expression levels of α- and β-tubulin at one and four hours (P˂0.05). mRNA level of EF-1α was enhanced in taxol-treated protomonts, but reduced in vinorelbine-treated cells when compared with the control (P˂0.05). While mRNA level of actin-cytoplasmic1 remained almost stable after treatment with both anti-tubulin drugs, mRNA expressions of other targeted genes- Rab-7, 40s ribosomal protein, and cathepsin were insignificantly down-regulated in both treatments when compared with control (P > 0.05). In general, target-specific taxol and vinorelbine were found to disturb the rate of encystation, cyst growth, and morphology. In addition, these drugs caused irregular mRNA expression of α- and β-tubulins. This study elucidates the constructive role of tubulins in protomont encystation and cyst proliferation.