The large amounts of chrome-tanned leather waste (CLTW) produced annually can be valorized by applying circular economy principles in various fields due to the valuable substances contained (mainly collagen). The main problem for the direct valorization of these wastes is the presence in their composition of dangerous substances, such as chromium. Thus, before being used as raw material in new processes, chrome-tanned leather waste must be subjected to a preliminary stage of chromium removal. In this article, we propose to identify the optimal working conditions for the extraction of chromium ions from chrome-tanned hides in the presence of oxalic acid with various concentrations, at various temperatures and contact times, so that the degree of collagen hydrolysis is minimal. In this sense, the response surface methodology (RSM) method was used to optimize the working conditions, to maximize the efficiency of chrome extraction from the leather, and to minimize the efficiency of collagen hydrolysis: An undesirable process. To optimize both the extraction yield (%) and the degree of hydrolysis (%), the key operational variables, namely oxalic acid concentration (%), contact time (%), and temperature (°C), were systematically adjusted using the Box–Behnken design within the response surface methodology (RSM). The most favorable extraction conditions were identified at an oxalic acid concentration of approximately 7%, a contact time close to 120 min, and a temperature near 49 °C. Under these optimized parameters, the hydrolysis degree remained very low, around 0.38%, indicating minimal degradation during the process.