One of the main global concerns is the usage and spread of antibiotic resistant Salmonella serovars. The animals, humans, and environmental components interact and contribute to the rapid emergence and spread of antimicrobial resistance, directly or indirectly. Therefore, this study aimed to determine antibiotic resistance (AR) profiles of Salmonella serotypes isolated from the environment, animals, and humans in South Africa by a systematic review and meta-analysis. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed to search four databases for studies published from 1980 to 2021, that reported the antibiotic resistance profiles of Salmonella serotypes isolated in South Africa. The AR was screened from 2930 Salmonella serotypes which were isolated from 6842 samples. The Western Cape province had high pooled prevalence estimates (PPE) of Salmonella isolates with AR profiles followed by North West, Gauteng, and Eastern Cape with 94.3%, 75.4%, 59.4%, and 46.2%, respectively. The high PPE and heterogeneity were observed from environmental samples [69.6 (95% CI: 41.7−88.3), Q = 303.643, I2 = 98.353, Q-P = 0.045], animals [41.9 (95% CI: 18.5–69.5), Q = 637.355, I2 = 98.745, Q-P = 0.577], as well as animals/environment [95.9 (95% CI: 5.4−100), Q = 55.253, I2 = 96.380, Q-P = 0.300]. The majority of the salmonella isolates were resistant to sulphonamides (92.0%), enrofloxacin and erythromycin (89.3%), oxytetracycline (77.4%), imipenem (72.6%), tetracycline (67.4%), as well as trimethoprim (52.2%), among the environment, animals, and humans. The level of multidrug-resistance recorded for Salmonella isolates was 28.5% in this review. This study has highlighted the occurrence of AR by Salmonella isolates from animals, humans, and environmental samples in South Africa and this calls for a consolidated “One Health” approach for antimicrobial resistance epidemiological research, as well as the formulation of necessary intervention measures to prevent further spread.