Considering the frequently large price fluctuations for soybean meal, an alternative is the increased use of locally produced high-protein ingredients. The objective of this study was to evaluate the effects of the total replacement of soybean meal with different sources of protein on the growth performance, nutrient digestibility, serum parameters, rumen fermentation parameters, and bacterial communities in growing lambs. Sixty sheep with similar body weights (38.46 ± 0.71 kg) were distributed to one of five treatments: soybean meal (SBM); cottonseed meal (COM); peanut meal (PEM); rapeseed meal (RAM); and distillers' dried grains with solubles (DDGS). The experiment lasted 62 days with a 10-day adaptation period and a 52-day growing period. The results indicated that the body weight and average daily gain were not affected by different protein sources (p > 0.05), but the dry matter intake of the SBM group was lower than that of the other groups (p < 0.05); otherwise, the feed efficiency was higher (p < 0.05). The digestion of dry matter was higher in the SBM, COM, and RAM groups than in the DDGS and PEM groups (p < 0.05). Meanwhile, compared to the other groups, the SBM group had the highest digestion of gross energy and crude protein (p < 0.05). In addition, the concentration of glutathione peroxidase was highest in the SBM group (p < 0.05). Regarding the rumen fermentation, the SBM group had the highest concentration of NH3-N (p < 0.05). The rumen bacterial community was not affected by treatments (p > 0.05). In conclusion, the total replacement of soybean meal with cottonseed, peanut, rapeseed, or DDGS reduced digestibility but did not impact the body weight or average daily gain of growing lambs and had no effect on the immune function and rumen bacterial community; thus, they can be used to substitute the soybean meal.