Solution processing of a bulk-heterojunction (BHJ) active layer in air with high relative humidity (RH) usually results in an inferior power conversion efficiency (PCE) of organic solar cells (OSCs). In this work, we demonstrate that such a challenge also exists in the state-of-the-art Y-series non-fullerene acceptor (NFA) based active layers such as PM6:Y6, PM6:L8-BO, and PM6:BTP-eC9. Moisture condensation during processing in high RH air should be the crucial factor that deteriorates the BHJ morphology. It was found that polymers PQSi705 and PTQ10, both comprising a quinoxaline–thiophene conjugated skeleton but with/without the 5% siloxane-terminated side chain, respectively, showed quite different humidity tolerance when casting the active layer. The PTQ10:Y6 active layer processed in a N2 glovebox, air with 65% RH, and air with 93% RH exhibited PCEs of 14.82%, 13.43%, and 12.22%, respectively, whereas the resulting PQSi705:Y6 active layers displayed almost identical PCEs of ∼16.1%, suggesting that PQSi705 with a siloxane-terminated side chain decoration afforded high humidity endurance in air-processing. The robustness of the PQSi705:Y6 active layer against moisture or water was also supported by investigations such as long-term storage (306 days) of OSCs in air, water immersion on the active layer surface, and exposing the active layer to boiling water vapor, all showing superior PCE retention. With m-TEH as the NFA, the PQSi705:m-TEH active layers processed in the N2 glovebox and 90% RH air exhibited almost identical PCEs of ∼18%. This is the highest efficiency so far reported for BHJ active layers fabricated in high RH air. Moreover, strong humidity tolerance in the air-processing was also achieved by more polymer donors or non-fullerene acceptors with siloxane-terminated side chains, suggesting certain universality. This work indicates that attaching a siloxane-terminated side chain on photoactive materials is a valuable chemical countermeasure to allow air-processing and withstand large variations in humidity.