Amide bond synthesis is ranked as the second most important challenge in key green chemistry research areas identified by the ACS Green Chemistry Institute. While developing more sustainable amide bond forming reactions has been in focus, significantly less attention has been given to human toxicity and environmental aspects of the underlying amine and acid substrates and their corresponding coupled products, a potentially important contribution to the overall sustainability of the amide-bond-forming reactions. Here, we explore biocatalytic amide bond formation from a safer-and-more-sustainable-by-design perspective in which commercially available amines and acids as well as their corresponding amide products were evaluated in silico based on potential human toxicity and environmental fate and exposure. This in silico filtering resulted in a panel of 188 amine and 54 acid building blocks that could be classified as safe, referred to herein as “safechems”. To enable couplings of safechems, we generated a panel of robust and promiscuous ancestral ATP-dependent amide bond synthetases (ABS) using McbA from Marinactinospora thermotolerans SCSIO 00652 as a template. Ancestral ABS enzymes exhibited complementary specificities in the coupling of a representative safechem subset of 17 amines and 16 acids while showing an increased thermostability of up to 20 °C compared to the extant biocatalyst. Finally, the pool of safechems and their corresponding amides were evaluated by USEtox (the UNEP-SETAC toxicity model), analysing not only the intrinsic properties of the compounds but evaluating their complete impact pathway including fate, exposure and effects. The amides were in general predicted as more toxic compared to the starting acids and amines through non-additive effects, emphasising that focusing on the toxicity of the building blocks alone is not sufficient to strive towards low human and ecotoxicity impact. Pursuing a safer and more sustainable by design perspective in the implementation of safechems did not prevent us from generating an array of novel products with potentially potent applications as exemplified here by enzymatic synthesis of substructures that are part of drug candidates for e.g. cancer treatment.