Background/Objectives: γ-Cyclodextrin metal–organic frameworks (γ-CD-MOFs) are biocompatible porous crystalline materials that combine the advantages of both γ-cyclodextrins (γ-CDs) and MOFs, making them promising carriers for drug delivery. However, drug loading efficiencies into γ-CD-MOFs achieved by impregnation method involves complex interactions that necessitate further systematic exploration. This study aimed to determine the impregnation conditions that significantly impact tenoxicam (TNX) loading into γ-CD-MOFs and its aqueous solubility, and to identify the optimal possible conditions for maximizing both. Methods: A three-factor, three-level (3³) Box–Behnken factorial design technique was utilized. Results: Statistical analysis showed that TNX/γ-CD-MOF molar ratio exerted a significant positive effect on drug loading, whereas loading temperature and time have an insignificant effect. Additionally, while loading TNX into γ-CD-MOFs increased its water solubility, variations in the loading parameters did not produce a significant effect on this solubility. The impregnation conditions obtained from the numerical optimization step were a drug/MOF molar ratio of 1.99:1 at 29 ± 0.5 °C for 6 h, which experimentally showed TNX loading of 12.2 ± 1.55%. A discrepancy between the predicted and experimental drug-loading results was observed suggesting that the fitted model does not fully capture the complexity of the system, highlighting the need for experimental verification. Conclusions: This work delivers new insights into the impregnation factors governing TNX loading into γ-CD-MOFs and establishes a foundational framework for the future optimization of CD-MOFs-based drug formulations.