The high recurrence rate of secondary cataract (SC) is caused by the intrinsic differentiation activity of residual lens epithelial cells after extra-capsular lens removal. The objective of this study was to identify changes in the microRNA (miRNA) expression profile during mouse SC formation and to selectively manipulate miRNA expression for potential therapeutic intervention. To model SC, mouse cataract surgery was performed and temporal changes in the miRNA expression pattern were determined by microarray analysis. To study the potential SC counterregulative effect of miRNAs, a lens capsular bag in vitro model was used. Within the first 3 wks after cataract surgery, microarray analysis demonstrated SC-associated expression pattern changes of 55 miRNAs. Of the identified miRNAs, miR-184 and miR-204 were chosen for further investigations. Manipulation of miRNA expression by the miR-184 inhibitor (anti-miR-184) and the precursor miRNA for miR-204 (pre-miR-204) attenuated SC-associated expansion and migration of lens epithelial cells and signs of epithelial to mesenchymal transition such as α-smooth muscle actin expression. In addition, pre-miR-204 attenuated SC-associated expression of the transcription factor Meis homeobox 2 (MEIS2). Examination of miRNA target binding sites for miR-184 and miR-204 revealed an extensive range of predicted target mRNA sequences that were also a target to a complex network of other SC-associated miRNAs with possible opposing functions. The identification of the SC-specific miRNA expression pattern together with the observed in vitro attenuation of SC by anti-miR-184 and pre-miR-204 suggest that miR-184 and miR-204 play a significant role in the control of SC formation in mice that is most likely regulated by a complex competitive RNA network.