In this study, we report the first supramolecular indicator-displacement assay (IDA) based on cucurbit[n]uril (CBn) hosts that is operational in blood serum. Rational design principles for host–guest chemosensing in competitively binding media were derived through detailed mathematical simulations. It was shown that currently known CBn-based chemosensing ensembles are not suited for use in highly competitive matrices such as blood serum. Conversely, the simulations indicated that a combination of cucurbit[8]uril (CB8) and an ultra-high affinity dye would be a promising IDA reporter pair for the detection of Alzheimer's drug memantine in blood serum. Therefore, a novel class of [2.2]paracyclophane-derived indicator dyes for the host CB8 was developed that possesses one of the highest host–guest affinities (K_a > 10¹² M⁻¹ in water) known in supramolecular host–guest chemistry, and which provides a large Stokes shift (up to 200 nm). The novel IDA was then tested for the detection of memantine in blood serum in a physiologically relevant sub- to low micromolar concentration range.