Protein searching and binding to specific sites on DNA is a fundamentally important process that marks the beginning of all major cellular transformations. While the dynamics of protein–DNA interactions in in vitro settings is well investigated, the situation is much more complex for in vivo conditions because the DNA molecules in live cells are packed into chromosomal structures where they are undergoing strong dynamic and conformational fluctuations. In this work, we present a theoretical investigation on the role of DNA looping and DNA conformational fluctuations in the protein target search. It is based on a discrete-state stochastic analysis that allows for explicit calculations of dynamic properties, which is also supplemented by Monte Carlo computer simulations. It is found that for stronger nonspecific interactions between DNA and proteins the search occurs faster on the DNA looped conformation in comparison with the unlooped conformation, and the fastest search is observed when the loop is formed near the target site. It is also shown that DNA fluctuations between the looped and unlooped conformations influence the search dynamics, and this depends on the magnitude of conformational transition rates and on which conformation is more energetically stable. Physical–chemical arguments explaining these observations are presented. Our theoretical study suggests that the geometry and conformational changes in DNA are additional factors that might efficiently control the gene regulation processes.