Poloxamer 188 (P188) is a triblock copolymer of the form polyethylene oxide–polypropylene oxide–polyethylene oxide (PEO–PPO–PEO). The center PPO block is hydrophobic, and the side PEO blocks are hydrophilic, resulting in surface-active properties. P188 has been used in the pharmaceutical industry as an excipient in various formulations and drug delivery systems. Although the chemical stability of P188 in the solid state has been reported, there are very few reports detailing the solution state stability. In this study, we report the solution state stability of P188 conducted to evaluate the effects of P188 concentration, temperature, pH and buffer type, and trace metals on chemical stability. The degradation chemistry of P188 and identification of degradation products was studied using various analytical techniques (ultraviolet, gas chromatography–mass spectrometry, and liquid chromatography-mass spectrometry). The degradation of P188 in solution was found to be strongly dependent on temperature, P188 concentration, and buffer type. For the first time, we report that in histidine buffer, oxidation of both P188 and histidine may occur at pharmaceutically relevant conditions. We observed degradation of both histidine and P188 as well as species formed from the mutual interactions of the degradation products from the 2 types of molecules.