Background/Objectives: The present study aims to highlight the possible significant changes due to the COVID-19 pandemic in the resistance of pathogens involved in cases of pediatric infections. Methods: This study included children hospitalized in the Pediatric Intensive Care Unit, Surgery and Pediatrics from a tertiary teaching hospital, during and after the COVID-19 period (2020-2023). Results: The research included 845 samples collected during 2020-2023, from 685 pediatric patients. A total of 937 bacterial isolates were obtained, of which 509 isolates (54.32%) were Gram-negative bacteria. Around 30% of all the pathogens were multidrug-resistant (MDR), with a statistically significant increase post-pandemic, in the case of the MDR Escherichia coli strains (p < 0.05). A very high percentage of MDR Acinetobacter spp. isolates was found, with an important, but not statistically significant, increase in the post-pandemic period. The highest percentage of the MDR Gram-positive pathogens was registered in the case of S. aureus strains (31.80%). Over 20% of the Coagulase-negative Staphylococci (CoNS) strains isolated between 2020 and 2023 were MDR, with an important increase in the post-COVID-19 period. The proportion of carbapenem-resistant Gram-negative pathogens significantly decreased in the post-COVID-19 period compared with the COVID-19 period (p < 0.05), especially in the case of the Klebsiella spp. strains. Conclusions: Our findings revealed the increase in the post-COVID-19 period of the prevalence of MDR strains of Acinetobacter spp., CoNS, and Escherichia coli isolated in pediatric patient samples and a significant decline in the trend of the carbapenem-resistant Gram-negative pathogens, which may be due to the testing rate and to the specific pathology of the pediatric patients hospitalized in the two periods.