Methods, systems, and computer readable media for copy-on-demand optimization for large writes are disclosed. According to one aspect, a method for copy on demand optimization for large writes includes, in a system having a source data storage entity and a destination data storage entity, receiving a write request to write data to a target portion of the source data storage entity, the target portion of the source data storage entity comprising at least one data storage block. The method includes determining whether the source data storage entity and the destination data storage entity are engaged in a backup operation in which data sufficient to synchronize the source data storage entity to the destination data storage entity is copied from the destination data storage entity to the source data storage entity, and if so, determining whether the target portion of the source data storage entity is not yet synchronized to the destination data storage entity. If the target portion of the source data storage entity is not yet synchronized to the destination data storage entity, a copy-on-demand operation is performed to synchronize the target portion of the source data storage entity to the destination data storage entity, where each data storage block within the target portion of the source data storage entity that will be completely overwritten as a result of the write request is not synchronized to the destination data storage entity. The write request to write data to the target portion of the source data storage entity is then processed.