The development of a new drilling fluid system with hydrate inhibition is of great significance for drilling safety in gas hydrate-bearing sediments. Considering the importance of the selection of a suitable thickener for drilling fluid systems under weak and strong driving forces, the hydrate inhibition of 0.1–0.5 wt% modified starch (MS), carboxymethylcellulose sodium (CMC), and xanthan gum (XG) aqueous solutions was studied. The applicability of these three thickeners were investigated through hydrate formation experiments, mesostructure observations, water activity tests, bubble retention observations, and rheological property tests. The results show that (1) under weak driving force, 0.3 wt% or higher concentration CMC and 0.3 wt% XG can almost completely inhibit hydrate formation due to the interactions between relatively small amounts of free water and CH4 molecules. Furthermore, the hydrate inhibition of higher XG concentrations was decreased due to their strong foam stability, leading to good contact between free water and CH4 molecules. Meanwhile, the hydrate inhibition of MS was weaker when compared with that of CMC and XG at the same concentrations. (2) Under strong driving force, the existence of the three 0.1–0.5 wt% thickeners could only slow down the hydrate formation rate, and hydrate inhibition due to XG was slightly better than that of the other two. This result implies that the effects of the different mesostructures on hydrate formation were severely weakened. Finally, (3) the tackifying effect of CMC was found to be stronger than that of XG and MS, and the rheological properties of the CMC solution were shown to be relatively weak compared to those of the XG and MS solutions; the CMC solution showed a more significant increase in viscosity with decreasing temperature, which is related to the differences in the mesostructures. Therefore, when the driving force of hydrate formation is relatively low, CMC is a good choice for the drilling fluid system when there is no requirement for cooling, while XG is more applicable for a system that needs cooling. In the case of a stronger driving force, XG is the optimal choice irrespective of whether the drilling fluid system needs cooling or not.