The "Renqing Changjue" pill (RQCJ), as an effective prescription of Traditional Tibetan Medicine (TTM), has been widely used in treating advanced gastroenteropathy diseases for over a thousand years. However, the toxicity and adverse effects of TTM have attracted increasing attention because heavy metals may be added as active ingredients. In this work, we introduced a robust model based on endogenous metabolism enabling the study of changes in copper (Cu), zinc (Zn), arsenic (As), mercury (Hg), and lead (Pb) concentrations and the mechanism between biofluids (blood and urine) and tissue (liver, kidney, spleen) samples from rats treated with RQCJ, along with metabolic changes after different treatment time points. Inductively coupled plasma-mass spectrometry was used to monitor the heavy metals. Slightly different trends of heavy metals were observed in rat metabolites. The levels of Hg, As, and Pb were clearly dose-dependent in the tissue and biofluid samples. Basic recovery of Hg and Pb was found after stopping treatment with RQCJ. The accumulation of As was more obvious in the blood, liver, kidney, and spleen; however, Hg was deposited in the kidney. Pb accumulated the most in the spleen. The concentrations of Cu and Zn were constant or accumulated to a certain extent, which could cause the body to have Cu and Zn metabolism disorders in the administration period. Our findings highlight how metal changes and effects on the mechanisms might contribute to the progression of understanding of the toxicity information for RQCJ. Therefore, precautions should be taken in the clinic to monitor the potential toxicity of RQCJ with long-term administration.