The indium(III)-catalyzed cascade cycloisomerization reaction of 1,5-enynes with pendant aryl nucleophiles is reported. The reaction proceeds in cascade, under mild reaction conditions, using InI3 (5 mol%) as catalyst with a range of 1,5-enynes furnished with aryl groups (phenyl and phenol) at the alkene (E and Z isomers) and with terminal and internal alkynes. Using 1-bromo-1,5-enynes a one-pot sequential indium-catalyzed cycloisomerization and palladium-catalyzed cross-coupling with triorganoindium reagents was developed. The double cyclization is stereospecific and operates via a biomimetic cascade cation-olefin through a 1,5-enyne cyclization (6-endo–dig) and subsequent C–C hydroarylation or a C–O phenoxycyclization. DFT computational studies on 1,5-enynyl aryl ethers support a two-step mechanism where the first stereoselective 1,5-enyne cyclization produce a non-classical carbocation intermediate that evolves to the tricyclic reaction product through a SEAr mechanism. Using this approach, a variety of tricyclic heterocycles such as benzo[b]chromenes, phenanthridines, xanthenes, and spiroheterocyclic compounds are efficiently synthesized with high atom economy.