Isoquinoline alkaloids, an important class of N‐based heterocyclic compounds, have attracted considerable attention from researchers worldwide since the early 19th century. Over the past 200 years, many compounds from this class were isolated, and most of them and their analogs possess various bioactivities. In this review, we survey the updated literature on bioactive alkaloids and highlight research achievements of this alkaloid class during the period of 2014–2018. We reviewed over 400 molecules with a broad range of bioactivities, including antitumor, antidiabetic and its complications, antibacterial, antifungal, antiviral, antiparasitic, insecticidal, anti‐inflammatory, antioxidant, neuroprotective, and other activities. This review should provide new indications or directions for the discovery of new and better drugs from the original naturally occurring isoquinoline alkaloids.