Exploring solid forms with low toxicity and high safety is a universal theme in drug research. This study developed a new cocrystal to optimize the severe hepatotoxicity of the first-line antituberculosis drug pyrazinamide (PZA). Baicalein (BCL) was chosen as the cocrystal former for its powerful hepatoprotective effect. The PZA–BCL cocrystal was structurally characterized by single-crystal X-ray diffraction (SCXRD), powder XRD (PXRD), differential scanning calorimetry–thermogravimetry (DSC-TG), and infrared (IR) spectroscopy. Meanwhile, the in vitro dissolution and in vivo pharmacokinetics and hepatotoxicity of the cocrystal were evaluated systematically. The results highlight that the BCL obtained tremendous improvements in water solubility, bioavailability, and hepatoprotective effect after cocrystal formation, hence almost removing the toxicity of PZA finally. Furthermore, it is worth noting that the molar ratio of 7:3 was first observed in the cocrystal, which is rare relative to the widely reported simple integer ratio of pharmaceutical cocrystals. The present research provides an interesting case for applying cocrystal technology in the field of drug safety.