Peste-des-Petits Ruminants Virus (PPRV) causes a highly contagious and severe infectious disease known as Peste-des-Petits Ruminants (PPR), resulting in significant mortality in both domestic and wild ruminants. An in-depth understanding of the molecular relationship between PPRV and susceptible hosts is essential for the prevention of PPR. The signaling lymphocytic-activation molecule (SLAM) acts as a key receptor in susceptible host species, mediating interactions with PPRV and triggering PPR in ruminants. This study offers an in-depth analysis of PPRV-susceptible host species as well as the identified SLAM amino acid sequences to date. Investigation reveals that nine families—Bovidae, Camelidae, Cervidae, Elephantidae, Suidae, Felidae, Canidae, Muridae, and Ceratopogonidae—have been affected by PPRV infection. Furthermore, a bioinformatics-based approach was proposed to screen the least common amino acid patterns (LCAP) in important SLAM receptor regions of known PPRV-susceptible species. Research findings reveal that 14 least common amino acid sites (LCAS) in SLAM amino acid sequences (I61, I63, S60, S70, K76, K78, I79, S81, L82, E123, N125, S127, V128, and F131) exhibit a prevalent similarity to LCAP across all known susceptible species. Comparative analysis of these 14 LCAP with SLAM nucleotide sequences from unknown susceptible ruminants to identify species at heightened risk of PPRV. In the result, 48 species from 20 different families across six orders were at potential risk of being infected with PPRV. This exploration suggests the feasibility of assessing potential hosts at high risk of PPRV infection through the LCAS screening technique. Moreover, it offers a means to anticipate and issue warnings regarding the likelihood of interspecies transmission. In conclusion, this study integrates molecular biology and bioinformatics, shedding light on PPRV infection dynamics and paving the way for predictive strategies to prevent the spread of this devastating disease among ruminant populations.