AbstractAntibody–drug conjugates (ADCs) are a growing class of chemotherapeutic agents that have yielded striking clinical successes. However, the efficacy of ADCs often suffers from issues associated with tumor heterogeneity and resistance. To overcome these problems, a new generation of ADCs comprising a single monoclonal antibody with multiple different payloads attached, termed multi‐payload ADCs, have been developed. Here we deploy multiple orthogonal site‐specific protein modification strategies to generate highly homogeneous multi‐functionalised antibody conjugates comprising up to four different functionalities installed at four unique sites on the antibody. This work, which includes the use of a site‐specific cyclopropenone (CPO)‐based reagent, represents the first example of a homogeneous multi‐payload ADC with a payload count greater than two, and thereby facilitates the development of the next generation of ADCs.