Nine new 1 : 1 co-crystals of caffeine with some halogenated nitroanilines and two nitrobenzoic acids have been synthesized. These new caffeine (CAF) co-crystals, with 4-nitroaniline (4NA), 4-fluoro-3-nitroaniline (4F3NA), 4-chloro-3-nitroaniline (4Cl3NA), 4-iodo-3-nitroaniline (4I3NA), 2-fluro-5-nitroaniline (2F5NA), 2-chloro-5-nitroaniline (2Cl5NA), 2-iodo-4-nitroaniline (2I4NA), 2,4-dinitrobenzoic acid (24DNB), 2-fluoro-5-nitrobenzoic acid (2F5NB), are characterized by single crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis and infrared spectroscopy. The co-crystals adopt a range of structures, namely two-dimensional (2D) flat layer, corrugated layer and 3D interlocked structures. The series of crystals allowed us to establish a structure–mechanical property relationship by using a simple mechanical deformation (qualitative) method. The 2D flat layer crystals (CAF/24DNB, CAF/2Cl5NA and CAF/2I4NA), which have strong intralayer and weak interlayer interactions show shear deformation behaviour, while those with weak intralayer interactions (CAF/4Cl3NA and CAF/4I3NA) show brittle fracture on application of a mechanical stress. The structures with corrugated layers (CAF/2F5NA) or 3D interlocked packing (CAF/NA, CAF/2F5NB and CAF/4F3NA) also show brittle behaviour. We also show the need for a wide initial search, targeting even the least expected synthons, to improve the efficiency of co-crystal screening.