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The study was conducted to determine the effect of agro-ecological zone, season of birth and sex on Nguni calves’ pre-weaning performance. Production indices such as birth weight (BW), weaning weight (WW), pre-weaning average daily gain (P-ADG) and pre-weaning gain (P-WG) were assessed in the different agro-ecological zones. Herd records on performance of 826 Nguni calves’ from nine Nguni herds representing different agro-ecological zones: arid zone (n = 217); semi-arid zone (n = 296); dry sub-humid zone (n = 118) and humid zone (n = 195) were used for the analysis of pre-weaning calf performance. General linear model (GLM) procedure of SAS (2013) was used to analyse data, whereas mean separation was conducted using Tukey’s HSD test. Agro-ecological zone had a great influence (P < 0.01) on performance levels arising from pasture conditions which were dependent on rain, temperature, topography and soil type. Fluctuations in WW, P-ADG and P-WG performance across agro-ecological zones depicted the sensitivity of Nguni calves’ to postnatal stress. Calves’ in humid zone had higher performance with 121.21 kg for WW, 96.83 kg for P-WG and 0.477 kg/day for P-ADG. The lowest WW (114.51 kg), P-WG (89.98 kg) and P-ADG (0.438 kg/day) were observed in arid zone. Male calves were heavier at weaning (128.18 kg), P-ADG (0.503 kg/day) and total gain (103.03 kg); however, similar BW of 25 kg was observed for both male and female calves. Season had a significant (P < 0.05) effect on BW, P-ADG and P-WG. The P-ADG was 0.461 kg/day for calves born in summer and 0.449 kg/day for calves born in winter season. Calves born in summer gained 94.69 kg and calves born in winter gained 92.10 kg. Summer calves gained 2.59 kg more than winter calves. Summer heifer calves performed poorly whilst summer male calves outperformed heifer calves in terms of WW, P-WG and P-ADG. Pre-weaned calves in humid zone outperformed all calves in other agro-ecological zones. It was concluded that acceptable levels of growth are achievable from Nguni cattle under the different agro-ecological zones of Limpopo province, South Africa.