The effects of Phyllanthus niruri hydroalcoholic extract and the isolated compounds quercetin, rutin, and gallic acid were examined in the mouse model of cyclophosphamide (CYP)-induced hemorrhagic cystitis (HC). HC was induced by a single CYP injection (300 mg/kg, IP), and the animals were evaluated 4 and 6 h after. Some animals were orally treated with the reference compound 2-mercaptoethane sodium sulfonate (Mesna) 80 mg/kg (30 min before CYP) and 160 mg/kg (2 h after CYP). Other groups were treated with P. niruri extract (30 and 50 mg/kg), or quercetin, rutin, and gallic acid (10 and 20 mg/kg), given orally, at the same intervals described for Mesna. P. niruri extract and its active components produced a significant attenuation of the nociception, edema, and hemorrhage evoked by CYP, which was similar to that seen for Mesna. Gallic acid and rutin displayed greater anti-inflammatory effects, whereas quercetin presented superior antinociceptive activities. Noteworthy is that P. niruri extract and compounds significantly reduced CYP-induced liver lipid peroxidation. Our results shed new light on the beneficial effects of P. niruri extract and its active compounds in attenuating the collateral effects elicited by the chemotherapeutic agent CYP.