In this work, we synthesized and investigated tetra- (PbPcF4) and hexadecafluorinated (PbPcF16) lead phthalocyanines. Their single crystal structures were refined for the first time. PbPcF4 crystallizes in stacks with all molecules facing in one direction identically to the monoclinic PbPc polymorph in the tetragonal space group I4, while PbPcF16 crystallizes in the triclinic P-1 space group. Moreover, the effect of fluorosubstitution on the structural features of thin films grown by organic molecular beam deposition (OMBD), vibrational and UV–visible optical absorption spectra is discussed. Apart from this, the chemiresistive sensor response of PbPcFx (x = 0, 4, 16) films to ammonia (1–5 ppm) in dependence on fluorination degree is also studied. It was shown that the sensor response to ammonia decreases in the order of PbPcF4 > PbPcF16 > PbPc. The nature of interaction between PbPcFx and ammonia molecules was studied using DFT calculations.