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Background Macrolide-induced resistance to clindamycin is a well-described mechanism leading to the misuse of clindamycin and hence to treatment failure. Herein, we determined the frequency and associated factors of inducible clindamycin resistance in Gram-positive cocci in a tertiary care hospital. Methods A cross-sectional descriptive study was carried out between January and December 2022. D tests were performed as recommended by EUCAST 2021 guidelines on 100 non-duplicate clinical isolates of Gram-positive cocci to determine the prevalence of methicillin resistance and inducible clindamycin resistance among the collected isolates. Results Of the 100 Gram-positive cocci isolates, 56 (56.0%), 17 (17.0%) and 27 (27.0%) were respectively coagulase-negative staphylococci, Staphylococcus aureus and Streptococcus spp. Among Streptococcus spp., Group D Streptococci (15.0%) were the most isolated. Methicillin-resistant Staphylococcus aureus (MRSA) represented 9 (53.0%) of S. aureus isolates. Constitutive (cMLSb) and inducible clindamycin resistance (iMLSb) phenotypes were detected in 36 (36.0%) and 14 (14,0%) of the isolates, with 38.4% and 13.7% of the S. aureus isolates exhibiting cMLSb and, iMLSb, respectively. The result of multivariate analysis showed that age groups, gender, type of samples, provenance, and bacteria, were not significantly associated with Gram-positive cocci iMLSb phenotype. Conclusion The study reported for the first time a high prevalence of inducible resistance of Gram-positive cocci strains to clindamycin in Niger Republic. This suggests the urgent need for the implementation of regular screening of these isolates and the wise use of clindamycin in clinical practice.