Piper nigrum and Piper longum are globally popular spices, listed in the catalog of medicinal food homology. Their fruits are abundant in amide alkaloids, exhibiting a wide range of biological activities. This paper provides a comprehensive review of the research on amide alkaloids from those two edible species, focusing on their activities and mechanisms of action. 239 amide alkaloids are summarized in this review, of which 97 exhibit anti-inflammatory, anti-tumor, and neuroprotective effects. The anti-inflammatory properties of amide alkaloids are associated with the ERK and NF-κB signaling pathways. Their anti-tumor effects are mediated through the Src/ERK/STAT3, ERK1/2, p38 MAPK, and Akt pathways. Additionally, the neuroprotective benefits are linked to the NGF/Trka/Akt/GSK3β signaling pathway. These findings suggest that P. nigrum and P. longum could be valuable for promoting human health care.