The objective of this study was to evaluate the nexus of bio-slurry (BS) and chemical fertilizer (CF) application, soil physico-chemical properties, and food safety of maize (Zea mays L.) grain. A field experiment was conducted at Hawassa University Research Farm, in Sidama Region, Ethiopia, under rain-fed conditions. The experiment consisted of three treatments, arranged in a randomized complete block design with three replications. The treatments were 100% BS (5 ton BS ha-1), 100% CF (90 kg N ha-1 + 30 kg P ha-1 + 13 kg S ha-1) and control. Soil samples were taken from 0–20 cm depth for the physicochemical analysis. Maize grain samples were also collected at harvest for the analysis of heavy metal concentration. Results show that the pre-experiment soil had a loam texture, moderately acidic pH, moderate OC and TN, high P, K and CEC. The mean concentrations of heavy metals in pre-experiment soil was below the permissible limit for arable land except Cd. Applying CF and BS increased soil pH, OC, TN, and K over the control. In contrast, applying BS and CF increased the concentrations of Ni (11.29) and Ni (12.71) and Co (5.87) in maize grain, respectively, which exceeded the FAO/WHO 2001 standards. Attributing to heavy metal concentration, this result signifies a potential health concern of applying BS and CF in maize cultivation for human consumption in the study sites. Therefore, pretreatment of BS and CF is important for the safe food quality of maize grains for human consumption.