A facile and efficient synthetic method for the stereoselective preparation of trisubstituted tetrahydro-β-carboline-fused diketopiperazine derivatives is reported. The methodology represents a one-pot four-step reaction, employing the Ugi four-component condensation which is followed by a Boc-deprotection, a Pictet–Spengler reaction and a final lactamization. All THBC-DKPs were obtained in good yields and excellent diastereomeric excess.