The use of drilling waste for land reclamation is a cost-effective way to improve soil fertility and to decrease landfills. However, the potential phytotoxic and cytotoxic effects of this waste on crops have not been investigated in detail. Here, we evaluated the toxicity of spent drilling fluids (SDFs) from a natural gas field using the non-target plant Zea mays L. (maize). Four different concentrations of SDFs (2%, 4%, 6%, and 8%, w/w) were used to test the toxic effects in two soils (aeolian and loessal). Different endpoints, including germination, root elongation, reactive oxygen species (ROS) accumulation, antioxidant activity, mitotic index, and chromosomal abnormalities, were used to test the effects of SDFs after four days of exposure. Higher levels (≥6%) of SDFs inhibited seed germination and root growth, and altered the oxygen status by increasing hydrogen peroxide (H2O2) and inhibiting superoxide ion (O2−) accumulation in the roots. SDFs-induced oxidative stress caused member damage, exacerbated cell injury, and reduced cell viability in the roots, compared with those untreated plants. The plants responded to high SDFs levels (≥6%) by upregulating antioxidants such as peroxidase, superoxide dismutase ascorbate peroxidase, and proline. A reduction in the mitotic index and induction of chromosomal abnormalities in root meristematic cells were indicators of the cytotoxicity of SDFs in maize seedlings. The upregulation of antioxidants due to the change of ROS and the induction of chromosomal abnormalities were more severe in roots grown in aeolian soil than in those grown in loessal soil. The present results provide insight into the mechanism underlying the phytotoxicity and cytotoxicity of SDFs and have implications for land reclamation to minimize deleterious effects on non-target crops.